NM_000257.4(MYH7):c.2585C>T (p.Ala862Val) AND Hypertrophic cardiomyopathy

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 12, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000464813.17

Allele description

NM_000257.4(MYH7):c.2585C>T (p.Ala862Val)

Genes:

LOC126861898:BRD4-independent group 4 enhancer GRCh37_chr14:23893609-23894808 [Gene]
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.4(MYH7):c.2585C>T (p.Ala862Val)

HGVS:

NC_000014.9:g.23424863G>A
NG_007884.1:g.15799C>T
NM_000257.4:c.2585C>TMANE SELECT
NP_000248.2:p.Ala862Val
LRG_384t1:c.2585C>T
LRG_384:g.15799C>T
NC_000014.8:g.23894072G>A
NM_000257.2:c.2585C>T
NM_000257.3:c.2585C>T

Protein change:

A862V

Links:

dbSNP: rs149576470

NCBI 1000 Genomes Browser:

rs149576470

Molecular consequence:

NM_000257.4:c.2585C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000546242	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 12, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22429680, 28408708, 32894683, 34935411, 27532257, 28492532
SCV001430822	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	no assertion criteria provided	Uncertain significance (Feb 4, 2019)	germline	research	PubMed (3) [See all records that cite these PMIDs] 23299917, 22429680, 28408708

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000546242

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 12, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001430822

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

no assertion criteria provided

Uncertain significance
(Feb 4, 2019)

germline

research

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical Utility of a Phenotype-Enhanced MYH7-Specific Variant Classification Framework in Hypertrophic Cardiomyopathy Genetic Testing.

Mattivi CL, Bos JM, Bagnall RD, Nowak N, Giudicessi JR, Ommen SR, Semsarian C, Ackerman MJ.

Circ Genom Precis Med. 2020 Oct;13(5):453-459. doi: 10.1161/CIRCGEN.120.003039. Epub 2020 Sep 7.

PubMed [citation]

PMID:: 32894683

Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy.

Khan RS, Pahl E, Dellefave-Castillo L, Rychlik K, Ing A, Yap KL, Brew C, Johnston JR, McNally EM, Webster G.

J Am Heart Assoc. 2022 Jan 4;11(1):e022854. doi: 10.1161/JAHA.121.022854. Epub 2021 Dec 22.

PubMed [citation]

PMID:: 34935411
PMCID:: PMC9075202

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000546242.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 862 of the MYH7 protein (p.Ala862Val). This variant is present in population databases (rs149576470, gnomAD 0.01%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 22429680, 28408708, 32894683, 34935411). ClinVar contains an entry for this variant (Variation ID: 36636). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV001430822.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

The MYH7 Ala862Val variant has been previously identified in 1 HCM proband with apical hypertrophy who also carried another variant in MYBPC3 (Santos et al., 2012). We identified this variant in a HCM proband of Lebanese descent, the variant was also found to segregate to 2 other affected family members (Ingles et al., 2017). The variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at low frequency. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Computational tool SIFT, and PolyPhen-2 predict this variant to be benign, however MutationTaster predicts this variant to be "disease causing". Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant is located in a mutational hotspot (PM1), is rare in the general population (PM2) and in silico tools predict the variant to be deleterious (PP3) but it has been only been identified in 1 HCM proband without additional variants, therefore we classify MYH7 Ala862Val as a variant of "uncertain significance".

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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