VCV000006896.44 - ClinVar

NM_003002.4(SDHD):c.242C>T (p.Pro81Leu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(26)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003002.4(SDHD):c.242C>T (p.Pro81Leu)

Variation ID: 6896 Accession: VCV000006896.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.1 11: 112088939 (GRCh38) [ NCBI UCSC ] 11: 111959663 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Jan 13, 2025	Oct 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003002.4:c.242C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002993.1:p.Pro81Leu	missense
NM_001276503.2:c.169+966C>T		intron variant
NM_001276504.2:c.125C>T	NP_001263433.1:p.Pro42Leu	missense
NM_001276506.2:c.242C>T	NP_001263435.1:p.Pro81Leu	missense
NR_077060.2:n.277C>T		non-coding transcript variant
NC_000011.10:g.112088939C>T
NC_000011.9:g.111959663C>T
NG_012337.3:g.7093C>T
NG_033145.1:g.2860G>A
LRG_9:g.7093C>T
LRG_9t1:c.242C>T	LRG_9p1:p.Pro81Leu
	O14521:p.Pro81Leu

... more HGVS ... less HGVS

Protein change

P81L, P42L

Other names

Canonical SPDI

NC_000011.10:112088938:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA016688 UniProtKB: O14521#VAR_010038 OMIM: 602690.0003 dbSNP: rs80338844 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SDHD		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	677	823

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Paragangliomas 1	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Mar 29, 2024	RCV000007303.22
Pheochromocytoma	Pathogenic (2)	criteria provided, single submitter	Sep 12, 2022	RCV000007304.19
Hereditary pheochromocytoma-paraganglioma	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jun 11, 2024	RCV000020519.22
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 17, 2024	RCV000162448.16
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Feb 14, 2024	RCV000216073.25
Carney-Stratakis syndrome Mitochondrial complex II deficiency, nuclear type 1 Paragangliomas 1 Pheochromocytoma	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763227.10
Mitochondrial complex II deficiency, nuclear type 1	Likely pathogenic (1)	criteria provided, single submitter	Jan 25, 2022	RCV002221470.11
Carney-Stratakis syndrome Cowden syndrome 3 Paragangliomas with sensorineural hearing loss Pheochromocytoma	Pathogenic (1)	criteria provided, single submitter	Jan 28, 2024	RCV002228002.12
Mitochondrial complex 2 deficiency, nuclear type 3	Pathogenic (1)	criteria provided, single submitter	Mar 9, 2024	RCV003472995.2
SDHD-related disorder	Pathogenic (1)	no assertion criteria provided	Apr 17, 2024	RCV004748507.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Paragangliomas 1 Pheochromocytoma Mitochondrial complex II deficiency, nuclear type 1 Carney-Stratakis syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893859.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Sep 21, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hereditary pheochromocytoma-paraganglioma (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711451.2 First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019	Publications: PubMed (8) PubMed: 25695889‚ 24436918‚ 21937622‚ 11897817‚ 17102085‚ 23175444‚ 11156372‚ 12811540 Comment: The p.Pro81Leu variant in SDHD has been reported in >25 individuals with paragan gliomas and/or pheochromocytomas (PGL/PCC), segregated with disease in at least 16 relatives … (more) The p.Pro81Leu variant in SDHD has been reported in >25 individuals with paragan gliomas and/or pheochromocytomas (PGL/PCC), segregated with disease in at least 16 relatives from 7 families (Xekouki 2015, Sridhara 2013, Yeap 2011, Baysal 200 2, Mannelli 2006, Astrom 2003). This variant, along with loss of heterozygosity, has also been found as a somatic change in the tumor of an individual with an i solated pheochromocytoma (Gimm 2000). It has also been reported by other clinica l laboratories in ClinVar (Variation ID 6896). This variant has also been identi fied in 3/126674 of European chromosomes by the Genome Aggregation Database (gno mAD, http:/gnomad.broadinstitute.org; dbSNP rs80338844). This frequency is low e nough to be consistent with the frequency of hereditary PGL/PCC syndrome in the general population. In summary, this variant meets criteria to be classified as pathogenic for hereditary paraganglioma-pheochromocytoma syndrome in an autosoma l dominant manner based upon segregation studies and presence in multiple affect ed individuals. ACMG/AMP Criteria applied: PS4, PP1_Strong (Richards 2015). (less) Number of individuals with the variant: 3
Pathogenic (Nov 01, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000605086.4 First in ClinVar: Sep 30, 2017 Last updated: Jan 08, 2022	Comment: The SDHD c.242C>T; p.Pro81Leu variant (rs80338844) is one of the most common variants reported in familial and sporadic cases of head and neck paraganglioma (PGL) … (more) The SDHD c.242C>T; p.Pro81Leu variant (rs80338844) is one of the most common variants reported in familial and sporadic cases of head and neck paraganglioma (PGL) (Andrews 2018, Astrom 2003, Baysal 2000, Baysal 2002, Sridhara 2013, Xekouki 2015). It has been reported to co-segregate with disease in several affected families (Astrom 2003, Baysal 2000, Xekouki 2015). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 6896), and it is observed on only six chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 81 is well conserved across a variety of species and computational algorithms (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Andrews KA et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018 Jun;55(6):384-394. Astrom K et al. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet. 2003 Aug;113(3):228-37. Baysal BE et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000 Feb 4;287(5454):848-51. Baysal BE et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet. 2002 Mar;39(3):178-83. Sridhara SK et al. Genetic testing in head and neck paraganglioma: who, what, and why? J Neurol Surg B Skull Base. 2013 Aug;74(4):236-40. Xekouki P et al. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J Clin Endocrinol Metab. 2015 May;100(5):E710-9. (less)
Pathogenic (Dec 06, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279171.11 First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023	Comment: Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on … (more) Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23175444, 15328326, 28748451, 25494863, 19454582, 24758185, 30375904, 29386252, 11156372, 26259135, 25014000, 11897817, 11343322, 11391798, 12811540, 19802898, 26916530, 11391796, 26113606, 25326637, 25695889, 22290790, 15235042, 14974914, 17102085, 15479192, 10657297, 28179334, 29341163, 24102379, 23433498, 21348866, 24436918, 29681642, 30658386, 29777207, 30050099, 30877234, 22575350, 29625052, 31492822, 32741965, 30787465, 33087929) (less)
Pathogenic (May 06, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004220344.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (16) PubMed: 24758185‚ 30050099‚ 11391796‚ 15479192‚ 19454582‚ 21937622‚ 10657297‚ 25494863‚ 11897817‚ 21348866‚ 24436918‚ 23433498‚ 30375904‚ 29625052‚ 30877234‚ 23175444 Comment: The frequency of this variant in the general population, 0.000021 (6/282810 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more) The frequency of this variant in the general population, 0.000021 (6/282810 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals/families with paraganglioma and/or pheochromocytoma (PMIDs: 30877234 (2019), 30375904 (2018), 29625052 (2018), 25494863 (2015), 24436918 (2013), 23433498 (2013), 21348866 (2012), 21348866 (2011), 19454582 (2009), 15479192 (2004), 11897817 (2002), 11391796 (2001), 10657297 (2000)), and is found to co-segregate with disease in multiple families (PMIDs: 11391796 (2001) and 21937622 (2011)). An experimental study using a humanized yeast construct has reported this variant results in oxidative growth, SDH activity, oxygen consumption and mtDNA mutability similar to WT (PMID: 23175444 (2013), however, studies using tumor tissue have demonstrated that this variant results in reduced enzyme activity (PMID: 24758185) and increased fumarate:succinate ratio (PMID: 24758185 (2014) and 30050099 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Oct 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Paragangliomas 1 Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004362302.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (33) PubMed: 8981955‚ 10657297‚ 11343322‚ 11391796‚ 11391798‚ 11897817‚ 12811540‚ 14974914‚ 15235042‚ 15328326‚ 15479192‚ 17102085‚ 19454582‚ 21348866‚ 21937622‚ 22290790‚ 22575350‚ 23433498‚ 23666964‚ 24102379‚ 24436918‚ 24758185‚ 25014000‚ 25326637‚ 25494863‚ 25695889‚ 29386252‚ 29625052‚ 29681642‚ 29777207‚ 30050099‚ 30375904‚ 31492822 Comment: This missense variant replaces proline with leucine at codon 81 of the SDHD protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces proline with leucine at codon 81 of the SDHD protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that succinate dehydrogenase complexes with this SDHD variant exhibit lower SDH enzyme activity observed via a higher succinate to fumarate metabolite ratio (PMID: 24758185, 25014000, 30050099). This variant has been reported in numerous individuals affected with pheochromocytoma/paraganglioma (PMID: 8981955, 10657297, 11343322, 11391796, 11391798, 11897817, 12811540, 14974914, 15235042, 15328326, 15479192, 17102085, 19454582, 21937622, 21348866, 22290790, 22575350, 23433498, 23666964, 24436918, 24102379, 25326637, 25494863, 25695889, 29386252, 29625052, 29681642, 29777207, 30050099, 30375904, 31492822). It has been also shown that this variant segregates with disease (PMID: 8981955, 11391796, 11897817, 15479192, 22575350, 25695889). This variant has been identified in 6/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Jan 28, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Carney-Stratakis syndrome Paragangliomas with sensorineural hearing loss Pheochromocytoma Cowden syndrome 3 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000287817.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024	Publications: PubMed (11) PubMed: 28492532‚ 10657297‚ 11391796‚ 11897817‚ 15479192‚ 19454582‚ 21348866‚ 21937622‚ 23433498‚ 24436918‚ 25494863 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the SDHD protein (p.Pro81Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the SDHD protein (p.Pro81Leu). This variant is present in population databases (rs80338844, gnomAD 0.006%). This missense change has been observed in individual(s) with head and neck paraganglioma (HNP) or pheochromocytoma (PMID: 10657297, 11391796, 11897817, 15479192, 19454582, 21348866, 21937622, 23433498, 24436918, 25494863). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6896). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 09, 2024)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Paragangliomas 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004933597.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 24758185‚ 28179334‚ 30050099‚ 29386252‚ 30877234‚ 32098148 Comment: This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24758185, 28179334, 30050099]. This variant has been reported in multiple individuals … (more) This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24758185, 28179334, 30050099]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29386252, 30877234, 30050099, 32098148]. (less)
Pathogenic (Feb 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004224505.2 First in ClinVar: Jan 06, 2024 Last updated: Dec 28, 2024	Publications: PubMed (7) PubMed: 10323245‚ 10657297‚ 11897817‚ 12811540‚ 25695889‚ 32741965‚ 34906457 Comment: PP1_strong, PP3, PP4, PM2_moderate, PS4_moderate
Pathogenic (Oct 17, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000212801.9 First in ClinVar: Mar 24, 2015 Last updated: Jan 13, 2025	Publications: PubMed (26) PubMed: 10657297‚ 11156372‚ 11343322‚ 11391796‚ 11391798‚ 11897817‚ 12811540‚ 15479192‚ 19454582‚ 21937622‚ 22241717‚ 22290790‚ 23175444‚ 23433498‚ 23666964‚ 24102379‚ 24758185‚ 25014000‚ 25494863‚ 30050099‚ 30375904‚ 30484866‚ 30951038‚ 31194233‚ 32741965‚ 33748650 Comment: The p.P81L pathogenic mutation (also known as c.242C>T), located in coding exon 3 of the SDHD gene, results from a C to T substitution at … (more) The p.P81L pathogenic mutation (also known as c.242C>T), located in coding exon 3 of the SDHD gene, results from a C to T substitution at nucleotide position 242. The proline at codon 81 is replaced by leucine, an amino acid with similar properties. This alteration has been described in numerous cases of familial paraganglioma/pheochromocytoma (PGL-PCC), multifocal PGL-PCC, and sporadic PGL-PCC (Baysal BE et al. Science. 2000 Feb;287(5454):848-51; Milunsky JM et al. Am. J. Med. Genet. 2001 May;100(4):311-4; Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Astrom K et al. Hum. Genet. 2003 Aug;113(3):228-37; Shulskaya MV et al. Int J Neurosci, 2018 Dec;128:1174-1179; Enríquez-Vega ME et al. Cir Cir, 2019;86:33-37; McCrary HC et al. JAMA Otolaryngol Head Neck Surg, 2019 07;145:641-646; Richter S et al. Genet Med, 2019 03;21:705-717; Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Smith JD et al. OTO Open Mar;5:2473974X21995453) and has been shown to segregate with disease in PGL kindreds (Badenhop RF et al. Genes Chromosomes Cancer. 2001 Jul;31(3):255-63; Yeap PM et al. J. Clin. Endocrinol. Metab. 2011 Dec;96(12):E2009-13). A study consisting of 170 individuals with SDHD mutations, p.P81L carriers had a significantly lower risk for pheochromocytoma compared to other SDHD mutations (p=0.031) and presented almost exclusively with head/neck PGLs (Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394). One study reported that this alteration results in an increased succinate:fumarate ratio and decreased SDHD enzymatic activity; although the alteration produced a false-negative result using succinate:fumarate ratio in a different study using enzymatic levels as a method for screening for SDH mutations in a tumor with loss of heterozygosity and reduced SDH activity (Canu L et al. J. Clin. Endorcinol. Metab. 2014 Jul;99(7):2321-6; Richter S et al. J. Clin. Endocrinol. Metab. 2014 Oct;99(10):3903-11). It is believed that both founder effects and mutation recurrence contribute to the prevalence of this alteration in North America (Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Astrom K et al. Hum. Genet. 2003 Aug;113(3):228-37). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Jan 21, 2014)	criteria provided, single submitter (Lee et al. (JAMA. 2014)) Method: clinical testing	Paragangliomas 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	UCLA Clinical Genomics Center, UCLA Study: CES Accession: SCV000255463.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Age: 40-49 years Sex: female Ethnicity/Population group: European Caucasian Testing laboratory: UCLA Clinical Genomics Center
Pathogenic (Aug 21, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698141.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (5) PubMed: 19454582‚ 12811540‚ 21937622‚ 25695889‚ 23175444 Comment: Variant summary: The SDHD c.242C>T (p.Pro81Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense change that does not lie within a … (more) Variant summary: The SDHD c.242C>T (p.Pro81Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense change that does not lie within a known functional domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121894 control chromosomes tested in ExAC and published control cohorts. The variant has been reported in numerous patients, and has been found segregating with disease in families as well as in sporadic, non-familial cases. Based on the literature, the variant is considered a founder mutation and a well-known pathogenic allele. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Paragangliomas with sensorineural hearing loss Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000782285.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018
Likely pathogenic (Jan 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial complex II deficiency, nuclear type 1 Affected status: unknown Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002499223.1 First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022	Comment: PS4, PM2, PP3 Secondary finding: yes
Pathogenic (Sep 12, 2022)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Hereditary Paraganglioma-Pheochromocytoma Syndrome Affected status: unknown Allele origin: germline	New York Genome Center Accession: SCV003925264.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Comment: The c.242C>T p.(Pro81Leu) variant identified in the SDHD gene is a known Pathogenic variant that has been reported in multiple familial and sporadic cases of … (more) The c.242C>T p.(Pro81Leu) variant identified in the SDHD gene is a known Pathogenic variant that has been reported in multiple familial and sporadic cases of head and neck paraganglioma or pheochromocytoma [PMID: 10657297, 29625052, 15479192, 30375904, 11391796, 11897817,30877234], and has been deposited in ClinVar as Pathogenic/Likely Pathogenic by multiple independent laboratories [ClinVar ID: 6896]. In one study, of 53 individuals with detailed clinical information and carrying the p.(Pro81Leu) variant, 15 were asymptomatic, 37 had head and neck paraganglioma (HNPGL) (two metastatic) and 1 had phaeochromocytoma and paraganglioma (PPGL). Authors concluded that the p.(Pro81Leu) variant carriers manifest almost exclusively with HNPGL, while other SDHD pathogenic variants predispose to both HNPGL and PPGL [PMID: 29386252]. The c.242C>T variant is observed in 8 out of 590,232 heterozygous alleles (no homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8) suggesting it is not a common benign variant in the populations represented in those databases. The variant is located in exon 3 of this 4-exon gene, and is predicted to replace an evolutionarily conserved Proline amino acid with Leucine at position 81 of the encoded protein. In silico predictions are in favor of damaging effect for p.(Pro81Leu) [REVEL score = 0.91]. Based on available evidence, the c.242C>T p.(Pro81Leu) variant identified in the SDHD gene is reported as Pathogenic. (less) Clinical Features: Atrial fibrillation (present) Zygosity: Single Heterozygote Secondary finding: yes
Pathogenic (Nov 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Paragangliomas 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175324.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (9) PubMed: 10657297‚ 11391796‚ 11897812‚ 19454582‚ 21348866‚ 21937622‚ 23433498‚ 25494863‚ 29386252 Comment: The SDHD c.242C>T variant is classified as Pathogenic (PM2, PP3, PP1_Strong) The SDHD c.242C>T variant is a single nucleotide change in exon 3/4 of the … (more) The SDHD c.242C>T variant is classified as Pathogenic (PM2, PP3, PP1_Strong) The SDHD c.242C>T variant is a single nucleotide change in exon 3/4 of the SDHD gene, which is predicted to change the amino acid proline at position 81 in the protein to leucine. The variant has been reported in many patients with paraganglioma and has been suggested to be a founder variant (PMID:10657297, 11391796, 11897812, 19454582,21348866, 23433498, 25494863) (PS4). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152182 sequenced alleles; highest frequency = 0.0029%, Non-Finnish European population) (PM2). This variant co-segregates with disease (PMID:21937622, 10657297, 29386252) (PP1_strong). Computational predictions strongly support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs80338844) and as disease causing in the HGMD database (CM000207). It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 6896). (less)
Pathogenic (Sep 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003825501.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Mar 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Paragangliomas 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004808089.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Mar 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial complex 2 deficiency, nuclear type 3 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004203091.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jun 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pheochromocytoma-paraganglioma (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004814331.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (33) PubMed: 8981955‚ 10657297‚ 11343322‚ 11391796‚ 11391798‚ 11897817‚ 12811540‚ 14974914‚ 15235042‚ 15328326‚ 15479192‚ 17102085‚ 19454582‚ 21348866‚ 21937622‚ 22290790‚ 22575350‚ 23433498‚ 23666964‚ 24102379‚ 24436918‚ 24758185‚ 25014000‚ 25326637‚ 25494863‚ 25695889‚ 29386252‚ 29625052‚ 29681642‚ 29777207‚ 30050099‚ 30375904‚ 31492822 Comment: This missense variant replaces proline with leucine at codon 81 of the SDHD protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces proline with leucine at codon 81 of the SDHD protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that succinate dehydrogenase complexes with this SDHD variant exhibit lower SDH enzyme activity observed via a higher succinate to fumarate metabolite ratio (PMID: 24758185, 25014000, 30050099). This variant has been reported in numerous individuals affected with pheochromocytoma/paraganglioma (PMID: 8981955, 10657297, 11343322, 11391796, 11391798, 11897817, 12811540, 14974914, 15235042, 15328326, 15479192, 17102085, 19454582, 21937622, 21348866, 22290790, 22575350, 23433498, 23666964, 24436918, 24102379, 25326637, 25494863, 25695889, 29386252, 29625052, 29681642, 29777207, 30050099, 30375904, 31492822). It has been also shown that this variant segregates with disease (PMID: 8981955, 11391796, 11897817, 15479192, 22575350, 25695889). This variant has been identified in 6/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less) Number of individuals with the variant: 9 Zygosity: Single Heterozygote
Pathogenic (Aug 01, 2003)	no assertion criteria provided Method: literature only	PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1 Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000027499.6 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 10657297‚ 11343322‚ 11391796‚ 12811540‚ 11897817‚ 11156372 Comment on evidence: In 5 families with autosomal dominant paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous C-to-T transition in the SDHD gene, resulting in a … (more) In 5 families with autosomal dominant paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous C-to-T transition in the SDHD gene, resulting in a pro81-to-leu (P81L) substitution. The proline at position 81 is conserved in human, Bos taurus, Ascaris, and Caenorhabditis elegans. Milunsky et al. (2001) found the P81L mutation in 3 of 7 families with hereditary paraganglioma. Since this mutation results in the elimination of a normally occurring restriction endonuclease site (MspI), Milunsky et al. (2001) developed a restriction enzyme assay to screen for this mutation. Badenhop et al. (2001) found the P81L mutation in an individual with paraganglioma who developed sensorineural hearing loss. The mutation was also found in 3 other family members who had only paraganglioma. In an analysis of 23 families with paragangliomas, Astrom et al. (2003) identified the P81L mutation in 14 (approximately 61%). P81L had been implicated both as a founder and as a recurrent mutation among U.S. families (Baysal et al., 2002). Haplotype analyses of the 14 P81L carrier families indicated that 5 lacked the founder haplotype, suggesting independent origin. Pheochromocytoma, Somatic Gimm et al. (2000) found the P81L mutation in the heterozygous state as a somatic mutation in tumor tissue from a patient with sporadic (nonfamilial) pheochromocytoma (see 171300). Flanking markers also showed loss of heterozygosity. (less)
Pathogenic (Aug 01, 2003)	no assertion criteria provided Method: literature only	PHEOCHROMOCYTOMA, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000027500.6 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 10657297‚ 11343322‚ 11391796‚ 12811540‚ 11897817‚ 11156372 Comment on evidence: In 5 families with autosomal dominant paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous C-to-T transition in the SDHD gene, resulting in a … (more) In 5 families with autosomal dominant paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous C-to-T transition in the SDHD gene, resulting in a pro81-to-leu (P81L) substitution. The proline at position 81 is conserved in human, Bos taurus, Ascaris, and Caenorhabditis elegans. Milunsky et al. (2001) found the P81L mutation in 3 of 7 families with hereditary paraganglioma. Since this mutation results in the elimination of a normally occurring restriction endonuclease site (MspI), Milunsky et al. (2001) developed a restriction enzyme assay to screen for this mutation. Badenhop et al. (2001) found the P81L mutation in an individual with paraganglioma who developed sensorineural hearing loss. The mutation was also found in 3 other family members who had only paraganglioma. In an analysis of 23 families with paragangliomas, Astrom et al. (2003) identified the P81L mutation in 14 (approximately 61%). P81L had been implicated both as a founder and as a recurrent mutation among U.S. families (Baysal et al., 2002). Haplotype analyses of the 14 P81L carrier families indicated that 5 lacked the founder haplotype, suggesting independent origin. Pheochromocytoma, Somatic Gimm et al. (2000) found the P81L mutation in the heterozygous state as a somatic mutation in tumor tissue from a patient with sporadic (nonfamilial) pheochromocytoma (see 171300). Flanking markers also showed loss of heterozygosity. (less)
Pathogenic (-)	no assertion criteria provided Method: research	Hereditary pheochromocytoma-paraganglioma Affected status: yes, unknown Allele origin: germline	Section on Medical Neuroendocrinolgy, National Institutes of Health Accession: SCV000599533.1 First in ClinVar: Sep 14, 2017 Last updated: Sep 14, 2017	Observation 1: Observation 2:
Pathogenic (Apr 17, 2024)	no assertion criteria provided Method: clinical testing	SDHD-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005361254.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The SDHD c.242C>T variant is predicted to result in the amino acid substitution p.Pro81Leu. This variant has previously been reported in multiple individuals and families … (more) The SDHD c.242C>T variant is predicted to result in the amino acid substitution p.Pro81Leu. This variant has previously been reported in multiple individuals and families with paraganglioma and pheochromocytoma (Baysal et al. 2000. PubMed ID: 10657297; Hensen et al. 2012. PubMed ID: 21348866; Sridhara et al. 2013. PubMed ID: 24436918; Dénes et al. 2015. PubMed ID: 25494863). This variant is also known as c.125C>T (p.Pro42Leu) using an alternative transcript (NM_001276504.1). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. In ClinVar, the SDHD variant is reported as pathogenic by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6896/). This variant is interpreted as pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Hereditary pheochromocytoma-paraganglioma Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000040976.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (8) PubMed: 10657297‚ 11156372‚ 11343322‚ 11391796‚ 11391798‚ 11897817‚ 12811540‚ 20301715 BookShelf: NBK1548 BookShelf: NBK1548
not provided (-)	no classification provided Method: phenotyping only	Hereditary pheochromocytoma-paraganglioma Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000607172.1 First in ClinVar: Oct 14, 2017 Last updated: Oct 14, 2017	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Age: 10-19 years Sex: male Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2017-04-04 Testing laboratory interpretation: Pathogenic
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Comment:

The p.Pro81Leu variant in SDHD has been reported in >25 individuals with paragan gliomas and/or pheochromocytomas (PGL/PCC), segregated with disease in at least 16 relatives from 7 families (Xekouki 2015, Sridhara 2013, Yeap 2011, Baysal 200 2, Mannelli 2006, Astrom 2003). This variant, along with loss of heterozygosity, has also been found as a somatic change in the tumor of an individual with an i solated pheochromocytoma (Gimm 2000). It has also been reported by other clinica l laboratories in ClinVar (Variation ID 6896). This variant has also been identi fied in 3/126674 of European chromosomes by the Genome Aggregation Database (gno mAD, http:/gnomad.broadinstitute.org; dbSNP rs80338844). This frequency is low e nough to be consistent with the frequency of hereditary PGL/PCC syndrome in the general population. In summary, this variant meets criteria to be classified as pathogenic for hereditary paraganglioma-pheochromocytoma syndrome in an autosoma l dominant manner based upon segregation studies and presence in multiple affect ed individuals. ACMG/AMP Criteria applied: PS4, PP1_Strong (Richards 2015).

Comment:

The SDHD c.242C>T; p.Pro81Leu variant (rs80338844) is one of the most common variants reported in familial and sporadic cases of head and neck paraganglioma (PGL) (Andrews 2018, Astrom 2003, Baysal 2000, Baysal 2002, Sridhara 2013, Xekouki 2015). It has been reported to co-segregate with disease in several affected families (Astrom 2003, Baysal 2000, Xekouki 2015). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 6896), and it is observed on only six chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 81 is well conserved across a variety of species and computational algorithms (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Andrews KA et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018 Jun;55(6):384-394. Astrom K et al. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet. 2003 Aug;113(3):228-37. Baysal BE et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000 Feb 4;287(5454):848-51. Baysal BE et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet. 2002 Mar;39(3):178-83. Sridhara SK et al. Genetic testing in head and neck paraganglioma: who, what, and why? J Neurol Surg B Skull Base. 2013 Aug;74(4):236-40. Xekouki P et al. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J Clin Endocrinol Metab. 2015 May;100(5):E710-9.

Comment:

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23175444, 15328326, 28748451, 25494863, 19454582, 24758185, 30375904, 29386252, 11156372, 26259135, 25014000, 11897817, 11343322, 11391798, 12811540, 19802898, 26916530, 11391796, 26113606, 25326637, 25695889, 22290790, 15235042, 14974914, 17102085, 15479192, 10657297, 28179334, 29341163, 24102379, 23433498, 21348866, 24436918, 29681642, 30658386, 29777207, 30050099, 30877234, 22575350, 29625052, 31492822, 32741965, 30787465, 33087929)

Comment:

The frequency of this variant in the general population, 0.000021 (6/282810 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals/families with paraganglioma and/or pheochromocytoma (PMIDs: 30877234 (2019), 30375904 (2018), 29625052 (2018), 25494863 (2015), 24436918 (2013), 23433498 (2013), 21348866 (2012), 21348866 (2011), 19454582 (2009), 15479192 (2004), 11897817 (2002), 11391796 (2001), 10657297 (2000)), and is found to co-segregate with disease in multiple families (PMIDs: 11391796 (2001) and 21937622 (2011)). An experimental study using a humanized yeast construct has reported this variant results in oxidative growth, SDH activity, oxygen consumption and mtDNA mutability similar to WT (PMID: 23175444 (2013), however, studies using tumor tissue have demonstrated that this variant results in reduced enzyme activity (PMID: 24758185) and increased fumarate:succinate ratio (PMID: 24758185 (2014) and 30050099 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

Comment:

This missense variant replaces proline with leucine at codon 81 of the SDHD protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that succinate dehydrogenase complexes with this SDHD variant exhibit lower SDH enzyme activity observed via a higher succinate to fumarate metabolite ratio (PMID: 24758185, 25014000, 30050099). This variant has been reported in numerous individuals affected with pheochromocytoma/paraganglioma (PMID: 8981955, 10657297, 11343322, 11391796, 11391798, 11897817, 12811540, 14974914, 15235042, 15328326, 15479192, 17102085, 19454582, 21937622, 21348866, 22290790, 22575350, 23433498, 23666964, 24436918, 24102379, 25326637, 25494863, 25695889, 29386252, 29625052, 29681642, 29777207, 30050099, 30375904, 31492822). It has been also shown that this variant segregates with disease (PMID: 8981955, 11391796, 11897817, 15479192, 22575350, 25695889). This variant has been identified in 6/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the SDHD protein (p.Pro81Leu). This variant is present in population databases (rs80338844, gnomAD 0.006%). This missense change has been observed in individual(s) with head and neck paraganglioma (HNP) or pheochromocytoma (PMID: 10657297, 11391796, 11897817, 15479192, 19454582, 21348866, 21937622, 23433498, 24436918, 25494863). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6896). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24758185, 28179334, 30050099]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29386252, 30877234, 30050099, 32098148].

Comment:

The p.P81L pathogenic mutation (also known as c.242C>T), located in coding exon 3 of the SDHD gene, results from a C to T substitution at nucleotide position 242. The proline at codon 81 is replaced by leucine, an amino acid with similar properties. This alteration has been described in numerous cases of familial paraganglioma/pheochromocytoma (PGL-PCC), multifocal PGL-PCC, and sporadic PGL-PCC (Baysal BE et al. Science. 2000 Feb;287(5454):848-51; Milunsky JM et al. Am. J. Med. Genet. 2001 May;100(4):311-4; Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Astrom K et al. Hum. Genet. 2003 Aug;113(3):228-37; Shulskaya MV et al. Int J Neurosci, 2018 Dec;128:1174-1179; Enríquez-Vega ME et al. Cir Cir, 2019;86:33-37; McCrary HC et al. JAMA Otolaryngol Head Neck Surg, 2019 07;145:641-646; Richter S et al. Genet Med, 2019 03;21:705-717; Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Smith JD et al. OTO Open Mar;5:2473974X21995453) and has been shown to segregate with disease in PGL kindreds (Badenhop RF et al. Genes Chromosomes Cancer. 2001 Jul;31(3):255-63; Yeap PM et al. J. Clin. Endocrinol. Metab. 2011 Dec;96(12):E2009-13). A study consisting of 170 individuals with SDHD mutations, p.P81L carriers had a significantly lower risk for pheochromocytoma compared to other SDHD mutations (p=0.031) and presented almost exclusively with head/neck PGLs (Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394). One study reported that this alteration results in an increased succinate:fumarate ratio and decreased SDHD enzymatic activity; although the alteration produced a false-negative result using succinate:fumarate ratio in a different study using enzymatic levels as a method for screening for SDH mutations in a tumor with loss of heterozygosity and reduced SDH activity (Canu L et al. J. Clin. Endorcinol. Metab. 2014 Jul;99(7):2321-6; Richter S et al. J. Clin. Endocrinol. Metab. 2014 Oct;99(10):3903-11). It is believed that both founder effects and mutation recurrence contribute to the prevalence of this alteration in North America (Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Astrom K et al. Hum. Genet. 2003 Aug;113(3):228-37). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

Variant summary: The SDHD c.242C>T (p.Pro81Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense change that does not lie within a known functional domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121894 control chromosomes tested in ExAC and published control cohorts. The variant has been reported in numerous patients, and has been found segregating with disease in families as well as in sporadic, non-familial cases. Based on the literature, the variant is considered a founder mutation and a well-known pathogenic allele. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The c.242C>T p.(Pro81Leu) variant identified in the SDHD gene is a known Pathogenic variant that has been reported in multiple familial and sporadic cases of head and neck paraganglioma or pheochromocytoma [PMID: 10657297, 29625052, 15479192, 30375904, 11391796, 11897817,30877234], and has been deposited in ClinVar as Pathogenic/Likely Pathogenic by multiple independent laboratories [ClinVar ID: 6896]. In one study, of 53 individuals with detailed clinical information and carrying the p.(Pro81Leu) variant, 15 were asymptomatic, 37 had head and neck paraganglioma (HNPGL) (two metastatic) and 1 had phaeochromocytoma and paraganglioma (PPGL). Authors concluded that the p.(Pro81Leu) variant carriers manifest almost exclusively with HNPGL, while other SDHD pathogenic variants predispose to both HNPGL and PPGL [PMID: 29386252]. The c.242C>T variant is observed in 8 out of 590,232 heterozygous alleles (no homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8) suggesting it is not a common benign variant in the populations represented in those databases. The variant is located in exon 3 of this 4-exon gene, and is predicted to replace an evolutionarily conserved Proline amino acid with Leucine at position 81 of the encoded protein. In silico predictions are in favor of damaging effect for p.(Pro81Leu) [REVEL score = 0.91]. Based on available evidence, the c.242C>T p.(Pro81Leu) variant identified in the SDHD gene is reported as Pathogenic.

Comment:

The SDHD c.242C>T variant is classified as Pathogenic (PM2, PP3, PP1_Strong) The SDHD c.242C>T variant is a single nucleotide change in exon 3/4 of the SDHD gene, which is predicted to change the amino acid proline at position 81 in the protein to leucine. The variant has been reported in many patients with paraganglioma and has been suggested to be a founder variant (PMID:10657297, 11391796, 11897812, 19454582,21348866, 23433498, 25494863) (PS4). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152182 sequenced alleles; highest frequency = 0.0029%, Non-Finnish European population) (PM2). This variant co-segregates with disease (PMID:21937622, 10657297, 29386252) (PP1_strong). Computational predictions strongly support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs80338844) and as disease causing in the HGMD database (CM000207). It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 6896).

Comment:

The SDHD c.242C>T variant is predicted to result in the amino acid substitution p.Pro81Leu. This variant has previously been reported in multiple individuals and families with paraganglioma and pheochromocytoma (Baysal et al. 2000. PubMed ID: 10657297; Hensen et al. 2012. PubMed ID: 21348866; Sridhara et al. 2013. PubMed ID: 24436918; Dénes et al. 2015. PubMed ID: 25494863). This variant is also known as c.125C>T (p.Pro42Leu) using an alternative transcript (NM_001276504.1). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. In ClinVar, the SDHD variant is reported as pathogenic by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6896/). This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Hereditary Paraganglioma-Pheochromocytoma Syndromes.	Adam MP	-	2023	PMID: 20301715
Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.	Garrett A	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34906457
Head and Neck Paragangliomas: Patterns of Otolaryngology Referrals for Genetic Testing Over 2 Decades.	Smith JD	OTO open	2021	PMID: 33748650
Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome.	Greenberg SE	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32741965
Natural History and Management of Familial Paraganglioma Syndrome Type 1: Long-Term Data from a Large Family.	Puliani G	Journal of clinical medicine	2020	PMID: 32098148
Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma-paraganglioma.	Bayley JP	Journal of medical genetics	2020	PMID: 31492822
Characterization of Malignant Head and Neck Paragangliomas at a Single Institution Across Multiple Decades.	McCrary HC	JAMA otolaryngology-- head & neck surgery	2019	PMID: 31194233
SDHD gene mutation in Mexican population with carotid body tumor.	Enríquez-Vega ME	Cirugia y cirujanos	2019	PMID: 30951038
Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma.	Ben Aim L	Journal of medical genetics	2019	PMID: 30877234
SDHx gene detection and clinical Phenotypic analysis of multiple paraganglioma in the head and neck.	Ding Y	The Laryngoscope	2019	PMID: 30484866
Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma.	Richter S	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30050099
The spectrum of SDHD mutations in Russian patients with head and neck paraganglioma.	Shulskaya MV	The International journal of neuroscience	2018	PMID: 30375904
Clinical progression and metachronous paragangliomas in a large cohort of SDHD germline variant carriers.	Heesterman BL	European journal of human genetics : EJHG	2018	PMID: 29777207
[SDHD gene mutation in Mexican population whit carotid body tumor].	Enríquez-Vega ME	Cirugia y cirujanos	2018	PMID: 29681642
Pathogenic Germline Variants in 10,389 Adult Cancers.	Huang KL	Cell	2018	PMID: 29625052
Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD.	Andrews KA	Journal of medical genetics	2018	PMID: 29386252
Potential Pitfalls of SDH Immunohistochemical Detection in Paragangliomas and Phaeochromocytomas Harbouring Germline SDHx Gene Mutation.	Santi R	Anticancer research	2017	PMID: 28179334
Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice.	Xekouki P	The Journal of clinical endocrinology and metabolism	2015	PMID: 25695889
Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.	Dénes J	The Journal of clinical endocrinology and metabolism	2015	PMID: 25494863
Clinical exome sequencing for genetic identification of rare Mendelian disorders.	Lee H	JAMA	2014	PMID: 25326637
Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency.	Richter S	The Journal of clinical endocrinology and metabolism	2014	PMID: 25014000
Pitfalls in genetic analysis of pheochromocytomas/paragangliomas-case report.	Canu L	The Journal of clinical endocrinology and metabolism	2014	PMID: 24758185
Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas.	McInerney-Leo AM	Clinical endocrinology	2014	PMID: 24102379
Genetic testing in head and neck paraganglioma: who, what, and why?	Sridhara SK	Journal of neurological surgery. Part B, Skull base	2013	PMID: 24436918
A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma.	Rattenberry E	The Journal of clinical endocrinology and metabolism	2013	PMID: 23666964
Paraganglioma of the carotid body: treatment strategy and SDH-gene mutations.	Fruhmann J	European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery	2013	PMID: 23433498
Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome.	Panizza E	Human molecular genetics	2013	PMID: 23175444
Coexistence of a pituitary macroadenoma and multicentric paraganglioma: a strange coincidence.	Varsavsky M	Endocrinologia y nutricion : organo de la Sociedad Espanola de Endocrinologia y Nutricion	2013	PMID: 22575350
Sporadic or familial head neck paragangliomas enrolled in a single center: clinical presentation and genotype/phenotype correlations.	Bacca A	Head & neck	2013	PMID: 22290790
Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients.	Piccini V	Endocrine-related cancer	2012	PMID: 22241717
High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands.	Hensen EF	Clinical genetics	2012	PMID: 21348866
Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect.	Yeap PM	The Journal of clinical endocrinology and metabolism	2011	PMID: 21937622
The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas.	Burnichon N	The Journal of clinical endocrinology and metabolism	2009	PMID: 19454582
SDH mutations in patients affected by paraganglioma syndromes: a personal experience.	Mannelli M	Annals of the New York Academy of Sciences	2006	PMID: 17102085
SDHB, SDHC, and SDHD mutation screen in sporadic and familial head and neck paragangliomas.	Mhatre AN	Clinical genetics	2004	PMID: 15479192
Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations.	Neumann HP	JAMA	2004	PMID: 15328326
The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features.	Badenhop RF	Journal of medical genetics	2004	PMID: 15235042
Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility.	Astuti D	Clinical endocrinology	2003	PMID: 14974914
Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect.	Astrom K	Human genetics	2003	PMID: 12811540
Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas.	Baysal BE	Journal of medical genetics	2002	PMID: 11897817
CP27 localization in the dental lamina basement membrane and in the stellate reticulum of developing teeth.	Diekwisch TG	The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society	2002	PMID: 11897812
Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene.	Taschner PE	Genes, chromosomes & cancer	2001	PMID: 11391798
Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss.	Badenhop RF	Genes, chromosomes & cancer	2001	PMID: 11391796
Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.	Milunsky JM	American journal of medical genetics	2001	PMID: 11343322
Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma.	Gimm O	Cancer research	2000	PMID: 11156372
Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.	Baysal BE	Science (New York, N.Y.)	2000	PMID: 10657297
Repositioning the hereditary paraganglioma critical region on chromosome band 11q23.	Baysal BE	Human genetics	1999	PMID: 10323245
Fine mapping of an imprinted gene for familial nonchromaffin paragangliomas, on chromosome 11q23.	Baysal BE	American journal of human genetics	1997	PMID: 8981955
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Text-mined citations for rs80338844 ...

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Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_003002.4(SDHD):c.242C>T (p.Pro81Leu)

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Text-mined citations for rs80338844 ...