VCV000030456.8 - ClinVar

NM_020433.5(JPH2):c.421T>C (p.Tyr141His)

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.

(4)

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
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020433.5(JPH2):c.421T>C (p.Tyr141His)

Variation ID: 30456 Accession: VCV000030456.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.12 20: 44160366 (GRCh38) [ NCBI UCSC ] 20: 42789006 (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	May 1, 2024	Jul 20, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_020433.5:c.421T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065166.2:p.Tyr141His	missense
NC_000020.11:g.44160366A>G
NC_000020.10:g.42789006A>G
NG_031867.1:g.32213T>C
LRG_394:g.32213T>C
LRG_394t1:c.421T>C	LRG_394p1:p.Tyr141His
	Q9BR39:p.Tyr141His

... more HGVS ... less HGVS

Protein change

Y141H

Other names

Canonical SPDI

NC_000020.11:44160365:A:G

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

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

ClinGen: CA129218 UniProtKB: Q9BR39#VAR_065472 OMIM: 605267.0002 dbSNP: rs387906897 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	883	894

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.
Hypertrophic cardiomyopathy 17	Pathogenic (1)	no assertion criteria provided	Jun 1, 2007	RCV000023409.2
Hypertrophic cardiomyopathy 1	Uncertain significance (1)	criteria provided, single submitter	Feb 29, 2020	RCV001256951.2
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Aug 26, 2020	RCV002326683.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jul 20, 2021	RCV001781303.3

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 (Feb 29, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 1 Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV001433482.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020
Likely pathogenic (Jul 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502096.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (2) PubMed: 17509612‚ 22389502 Number of individuals with the variant: 1 Secondary finding: no
Uncertain significance (Aug 26, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002629031.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 17509612‚ 22389502 Comment: The p.Y141H variant (also known as c.421T>C), located in coding exon 2 of the JPH2 gene, results from a T to C substitution at nucleotide … (more) The p.Y141H variant (also known as c.421T>C), located in coding exon 2 of the JPH2 gene, results from a T to C substitution at nucleotide position 421. This variant was reported in one sporadic hypertrophic cardiomyopathy (HCM) case, and functional studies indicate that this alteration may impact protein function (Landstrom AP et al. J. Mol. Cell. Cardiol., 2007 Jun;42:1026-35; Woo JS et al. J. Biol. Chem., 2012 Apr;287:14336-48). The tyrosine at codon 141 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Pathogenic (Jun 01, 2007)	no assertion criteria provided Method: literature only	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC 17 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044700.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 17509612 Comment on evidence: In a 33-year-old man who was diagnosed at age 24 years with hypertrophic cardiomyopathy (CMH17; 613873), Landstrom et al. (2007) identified heterozygosity for a mutation … (more) In a 33-year-old man who was diagnosed at age 24 years with hypertrophic cardiomyopathy (CMH17; 613873), Landstrom et al. (2007) identified heterozygosity for a mutation in exon 2 of the JPH2 gene, resulting in a tyr141-to-his (Y141H) substitution at a conserved residue. The mutation was not identified in 1,000 Caucasian reference alleles. Studies in transfected H9c2 cardiomyocytes showed an altered localization pattern with respect to the sarcoplasmic reticulum (SR) and significant hypertrophy (2- to 3-fold) compared to wildtype. Analysis of transfected HL-1 cardiomyocytes indicated decreased spontaneous calcium release from the SR, suggesting that excitation-contraction process was disrupted in cells expressing Y141H. At presentation, the patient had dyspnea, palpitations, angina, and a non-Q-wave myocardial infarction; he underwent placement of a pacemaker and an implantable cardioverter-defibrillator. There was no family history of CMH or sudden cardiac death. (less)

Comment:

The p.Y141H variant (also known as c.421T>C), located in coding exon 2 of the JPH2 gene, results from a T to C substitution at nucleotide position 421. This variant was reported in one sporadic hypertrophic cardiomyopathy (HCM) case, and functional studies indicate that this alteration may impact protein function (Landstrom AP et al. J. Mol. Cell. Cardiol., 2007 Jun;42:1026-35; Woo JS et al. J. Biol. Chem., 2012 Apr;287:14336-48). The tyrosine at codon 141 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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
Hypertrophy in skeletal myotubes induced by junctophilin-2 mutant, Y141H, involves an increase in store-operated Ca2+ entry via Orai1.	Woo JS	The Journal of biological chemistry	2012	PMID: 22389502
Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.	Landstrom AP	Journal of molecular and cellular cardiology	2007	PMID: 17509612

Text-mined citations for rs387906897 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_020433.5(JPH2):c.421T>C (p.Tyr141His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387906897 ...