VCV001709506.8 - ClinVar

NM_004168.4(SDHA):c.1283_1298del (p.Gln428fs)

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.

(5)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004168.4(SDHA):c.1283_1298del (p.Gln428fs)

Variation ID: 1709506 Accession: VCV001709506.8

Type and length

Deletion, 16 bp

Location

Cytogenetic: 5p15.33 5: 236447-236462 (GRCh38) [ NCBI UCSC ] 5: 236562-236577 (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	Oct 15, 2022	May 1, 2024	Sep 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004168.4:c.1283_1298del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004159.2:p.Gln428fs	frameshift
NM_001294332.2:c.1139_1154del	NP_001281261.1:p.Gln380fs	frameshift
NM_001330758.2:c.1283_1298del	NP_001317687.1:p.Gln428fs	frameshift
NM_004168.2:c.1283_1298del16
NC_000005.10:g.236450_236465del
NC_000005.9:g.236565_236580del
NG_012339.1:g.23210_23225del
LRG_315:g.23210_23225del
LRG_315t1:c.1283_1298del	LRG_315p1:p.Gln428fs

... more HGVS ... less HGVS

Protein change

Q380fs, Q428fs

Other names

Canonical SPDI

NC_000005.10:236446:GCCAGGATCAGATTGTGCC:GCC

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.

Links

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.
SDHA		-	-	GRCh38 GRCh37	2739	2898

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 5	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 12, 2023	RCV002289321.3
Mitochondrial complex II deficiency, nuclear type 1 Paragangliomas 5	Pathogenic (1)	criteria provided, single submitter	Dec 27, 2021	RCV003097776.3
Dilated cardiomyopathy 1GG	Pathogenic (1)	criteria provided, single submitter	May 3, 2023	RCV003475330.1
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Sep 5, 2023	RCV003340474.2

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 (Jun 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Paragangliomas 5 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580062.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS4_SUP, PM2_SUP, PP1	Number of individuals with the variant: 1 Sex: female
Pathogenic (Jan 12, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Paragangliomas 5 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV003836635.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (May 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1GG Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004200654.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Dec 27, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Paragangliomas 5 Mitochondrial complex II deficiency, nuclear type 1 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: SCV003459951.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 28384794‚ 22974104‚ 24781757 Comment: For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with clinical features of paraganglioma-pheochromocytoma … (more) For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with clinical features of paraganglioma-pheochromocytoma syndromes (PMID: 28384794). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln428Profs*37) in the SDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). (less)
Pathogenic (Sep 05, 2023)	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: SCV004059193.2 First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 28384794‚ 29978154 Comment: The c.1283_1298del16 pathogenic mutation, located in coding exon 10 of the SDHA gene, results from a deletion of 16 nucleotides at nucleotide positions 1283 to … (more) The c.1283_1298del16 pathogenic mutation, located in coding exon 10 of the SDHA gene, results from a deletion of 16 nucleotides at nucleotide positions 1283 to 1298, causing a translational frameshift with a predicted alternate stop codon (p.Q428Pfs*37). This variant has been reported in a male diagnosed with bilateral pheochromocytomas (Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212; Maniam P et al. J Endocr Soc, 2018 Jul;2:806-816). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with clinical features of paraganglioma-pheochromocytoma syndromes (PMID: 28384794). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln428Profs*37) in the SDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757).

Comment:

The c.1283_1298del16 pathogenic mutation, located in coding exon 10 of the SDHA gene, results from a deletion of 16 nucleotides at nucleotide positions 1283 to 1298, causing a translational frameshift with a predicted alternate stop codon (p.Q428Pfs*37). This variant has been reported in a male diagnosed with bilateral pheochromocytomas (Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212; Maniam P et al. J Endocr Soc, 2018 Jul;2:806-816). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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
Pathogenicity and Penetrance of Germline SDHA Variants in Pheochromocytoma and Paraganglioma (PPGL).	Maniam P	Journal of the Endocrine Society	2018	PMID: 29978154
Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.	Bausch B	JAMA oncology	2017	PMID: 28384794
SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors.	Renkema GH	European journal of human genetics : EJHG	2015	PMID: 24781757
SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors.	Italiano A	BMC cancer	2012	PMID: 22974104

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004168.4(SDHA):c.1283_1298del (p.Gln428fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...