VCV000549514.50 - ClinVar

NM_005327.7(HADH):c.643C>A (p.Pro215Thr)

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.

(10)

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.

Conflicting classifications of pathogenicity
Uncertain significance(4); Uncertain risk allele(1); Likely benign(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005327.7(HADH):c.643C>A (p.Pro215Thr)

Variation ID: 549514 Accession: VCV000549514.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q25 4: 108027694 (GRCh38) [ NCBI UCSC ] 4: 108948850 (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	Jul 21, 2018	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005327.7:c.643C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005318.6:p.Pro215Thr	missense
NM_001184705.2:c.643C>A
NM_001184705.4:c.643C>A	NP_001171634.3:p.Pro215Thr	missense
NM_001331027.2:c.655C>A	NP_001317956.2:p.Pro219Thr	missense
NC_000004.12:g.108027694C>A
NC_000004.11:g.108948850C>A
NG_008156.2:g.42911C>A

... more HGVS ... less HGVS

Protein change

P215T, P219T

Other names

Canonical SPDI

NC_000004.12:108027693:C:A

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.

0.00160 (A)

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

1000 Genomes Project 0.00160

Exome Aggregation Consortium (ExAC) 0.00167

1000 Genomes Project 30x 0.00172

The Genome Aggregation Database (gnomAD) 0.00198

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00269

Trans-Omics for Precision Medicine (TOPMed) 0.00330

Links

dbSNP: rs140413151 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.
HADH		-	-	GRCh38 GRCh37	321	351

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.
Monogenic diabetes	Uncertain significance (1)	criteria provided, single submitter	Mar 31, 2017	RCV000664101.5
Deficiency of 3-hydroxyacyl-CoA dehydrogenase Hyperinsulinemic hypoglycemia, familial, 4	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000764523.4
not provided	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000872937.28
Deficiency of 3-hydroxyacyl-CoA dehydrogenase	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 31, 2024	RCV001082981.17
Hyperinsulinemic hypoglycemia, familial, 4	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001145823.6
not specified	Likely benign (1)	criteria provided, single submitter	Dec 3, 2021	RCV001816664.5
Hyperinsulinemic hypoglycemia	Uncertain risk allele (1)	criteria provided, single submitter	-	RCV003222089.2
HADH-related disorder	Likely benign (1)	no assertion criteria provided	Oct 11, 2022	RCV003953224.2

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.
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of 3-hydroxyacyl-CoA dehydrogenase Hyperinsulinemic hypoglycemia, familial, 4 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000895606.1 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
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hyperinsulinemic hypoglycemia, familial, 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001306520.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Deficiency of 3-hydroxyacyl-CoA dehydrogenase Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001306521.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Likely benign (May 28, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001779548.1 First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021	Comment: 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: 32876354, … (more) 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: 32876354, 25007923) (less)
Likely benign (Dec 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002071093.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: This sequence change does not appear to have been previously described in individuals with HADH-related disorders. This sequence change has been described in the gnomAD … (more) This sequence change does not appear to have been previously described in individuals with HADH-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.014% (dbSNP rs140413151). The p.Pro215Thr change affects a highly conserved amino acid residue located in a domain of the HADH protein that is not known to be functional. The p.Pro215Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Pro215Thr change remains unknown at this time. (less)
Uncertain significance (Mar 31, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Monogenic diabetes Affected status: unknown Allele origin: unknown	Personalized Diabetes Medicine Program, University of Maryland School of Medicine Study: Personalized Diabetes Medicine Program Accession: SCV000787553.2 First in ClinVar: Jul 21, 2018 Last updated: Dec 11, 2022	Other databases http://www.type2diabetesgenetics… http://www.type2diabetesgenetics.org/variantSearch/launchAVariantSearch/?filters=%5B%7B%22dataset%22%3A%22ExSeq_19k_mdv33%22%2C%22value%22%3A%220%22%2C%22prop%22%3A%22MAC%22%2C%22comparator%22%3A%22%3E%22%2C%22phenotype%22%3A%22T2D%22%7D%2C%7B%22prop%22%3A%22chromosome%22%2C%22value%22%3A%224%3A108948850-108948850%22%2C%22comparator%22%3A%22%3D%22%7D%5D Comment: ACMG Criteria:PP3 (11 predictors), BS2 (18 cases and 25 controls in type2diabetesgenetics.org for AD monogenic diabetes; two homozygotes in ExAC) Number of individuals with the variant: 2
Uncertain risk allele (-)	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1) Method: research	Hyperinsulinemic hypoglycemia (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV003915740.1 First in ClinVar: Apr 23, 2023 Last updated: Apr 23, 2023	Publications: PubMed (3) PubMed: 34547194‚ 34055426‚ 29280746 Comment: Potent mutations in HADH gene are associated with congenital hyperinsulinism, which leads to recurrent hypoglycemia. The condition is exacerbated by stress, fasting or excessive dietary … (more) Potent mutations in HADH gene are associated with congenital hyperinsulinism, which leads to recurrent hypoglycemia. The condition is exacerbated by stress, fasting or excessive dietary protein. May respond well to diazoxide. However, the role of this particular variant rs140413151 in congenital hyperinsulinism is yet to be ascertained. (less)
Likely benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Deficiency of 3-hydroxyacyl-CoA dehydrogenase Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001014836.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001154224.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: HADH: BS2 Number of individuals with the variant: 6
Likely benign (Oct 11, 2022)	no assertion criteria provided Method: clinical testing	HADH-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004767200.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change does not appear to have been previously described in individuals with HADH-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.014% (dbSNP rs140413151). The p.Pro215Thr change affects a highly conserved amino acid residue located in a domain of the HADH protein that is not known to be functional. The p.Pro215Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Pro215Thr change remains unknown at this time.

Comment:

Potent mutations in HADH gene are associated with congenital hyperinsulinism, which leads to recurrent hypoglycemia. The condition is exacerbated by stress, fasting or excessive dietary protein. May respond well to diazoxide. However, the role of this particular variant rs140413151 in congenital hyperinsulinism is yet to be ascertained.

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
Congenital hyperinsulinism: recent updates on molecular mechanisms, diagnosis and management.	Giri D	Journal of pediatric endocrinology & metabolism : JPEM	2021	PMID: 34547194
Genotyping of ABCC8, KCNJ11, and HADH in Iranian Infants with Congenital Hyperinsulinism.	Hashemian S	Case reports in endocrinology	2021	PMID: 34055426
Congenital Hyperinsulinism: Diagnosis and Treatment Update.	Demirbilek H	Journal of clinical research in pediatric endocrinology	2017	PMID: 29280746
http://www.type2diabetesgenetics.org/variantSearch/launchAVariantSearch/?filters=%5B%7B%22dataset%22%3A%22ExSeq_19k_mdv33%22%2C%22value%22%3A%220%22%2C%22prop%22%3A%22MAC%22%2C%22comparator%22%3A%22%3E%22%2C%22phenotype%22%3A%22T2D%22%7D%2C%7B%22prop%22%3A%22chromosome%22%2C%22value%22%3A%224%3A108948850-108948850%22%2C%22comparator%22%3A%22%3D%22%7D%5D	-	-	-	-

Text-mined citations for rs140413151 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_005327.7(HADH):c.643C>A (p.Pro215Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140413151 ...