VCV003230902.1 - ClinVar

NM_000257.4(MYH7):c.2738T>C (p.Ile913Thr)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000257.4(MYH7):c.2738T>C (p.Ile913Thr)

Variation ID: 3230902 Accession: VCV003230902.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q11.2 14: 23424091 (GRCh38) [ NCBI UCSC ] 14: 23893300 (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	May 1, 2024	May 1, 2024	Jan 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000257.4:c.2738T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000248.2:p.Ile913Thr	missense
NM_001407004.1:c.2738T>C	NP_001393933.1:p.Ile913Thr	missense
NC_000014.9:g.23424091A>G
NC_000014.8:g.23893300A>G
NG_007884.1:g.16571T>C
LRG_384:g.16571T>C
LRG_384t1:c.2738T>C	LRG_384p1:p.Ile913Thr

... more HGVS ... less HGVS

Protein change

I913T

Other names

Canonical SPDI

NC_000014.9:23424090: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.

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.
MYH7		No evidence available	No evidence available	GRCh38 GRCh37	3643	4923

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	Likely pathogenic (1)	criteria provided, single submitter	Jan 12, 2024	RCV004523016.1

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.
Likely pathogenic (Jan 12, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005033845.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 25132132‚ 27532257‚ 28408708‚ 28790153 Comment: The p.I913T variant (also known as c.2738T>C), located in coding exon 21 of the MYH7 gene, results from a T to C substitution at nucleotide … (more) The p.I913T variant (also known as c.2738T>C), located in coding exon 21 of the MYH7 gene, results from a T to C substitution at nucleotide position 2738. The isoleucine at codon 913 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Wang J et al. Eur J Heart Fail, 2014 Sep;16:950-7; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:; Walsh R et al. Genet Med, 2017 Feb;19:192-203). This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)

Comment:

The p.I913T variant (also known as c.2738T>C), located in coding exon 21 of the MYH7 gene, results from a T to C substitution at nucleotide position 2738. The isoleucine at codon 913 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Wang J et al. Eur J Heart Fail, 2014 Sep;16:950-7; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:; Walsh R et al. Genet Med, 2017 Feb;19:192-203). This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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
Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing.	Burns C	Circulation. Cardiovascular genetics	2017	PMID: 28790153
Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications.	Ingles J	Circulation. Cardiovascular genetics	2017	PMID: 28408708
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy.	Wang J	European journal of heart failure	2014	PMID: 25132132

Text-mined citations for this variant ...

Record last updated May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000257.4(MYH7):c.2738T>C (p.Ile913Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...