VCV002586440.3 - ClinVar

NM_020433.5(JPH2):c.1837G>A (p.Glu613Lys)

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.

(2)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020433.5(JPH2):c.1837G>A (p.Glu613Lys)

Variation ID: 2586440 Accession: VCV002586440.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.12 20: 44115838 (GRCh38) [ NCBI UCSC ] 20: 42744478 (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 28, 2023	May 1, 2024	Jul 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020433.5:c.1837G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065166.2:p.Glu613Lys	missense
NC_000020.11:g.44115838C>T
NC_000020.10:g.42744478C>T
NG_031867.1:g.76741G>A
LRG_394:g.76741G>A
LRG_394t1:c.1837G>A	LRG_394p1:p.Glu613Lys

... more HGVS ... less HGVS

Protein change

E613K

Other names

Canonical SPDI

NC_000020.11:44115837: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.

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.
JPH2		-	-	GRCh38 GRCh37	884	895

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.
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jul 17, 2023	RCV003377962.2
JPH2-related disorder	Uncertain significance (1)	criteria provided, single submitter	May 16, 2023	RCV003397015.4

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 (May 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	JPH2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104624.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The JPH2 c.1837G>A variant is predicted to result in the amino acid substitution p.Glu613Lys. To our knowledge, this variant has not been reported in the … (more) The JPH2 c.1837G>A variant is predicted to result in the amino acid substitution p.Glu613Lys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Jul 17, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004053104.2 First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 30531895 Comment: The p.E613K variant (also known as c.1837G>A), located in coding exon 4 of the JPH2 gene, results from a G to A substitution at nucleotide … (more) The p.E613K variant (also known as c.1837G>A), located in coding exon 4 of the JPH2 gene, results from a G to A substitution at nucleotide position 1837. The glutamic acid at codon 613 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Thomson KL et al. Genet Med, 2019 Jul;21:1576-1584). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The JPH2 c.1837G>A variant is predicted to result in the amino acid substitution p.Glu613Lys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

The p.E613K variant (also known as c.1837G>A), located in coding exon 4 of the JPH2 gene, results from a G to A substitution at nucleotide position 1837. The glutamic acid at codon 613 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Thomson KL et al. Genet Med, 2019 Jul;21:1576-1584). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield.	Thomson KL	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30531895

Text-mined citations for this variant ...

Record last updated May 19, 2024

ClinVar Genomic variation as it relates to human health

NM_020433.5(JPH2):c.1837G>A (p.Glu613Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...