Submissions for variant NM_000257.4(MYH7):c.1012G>A (p.Val338Met)

dbSNP: rs727503271

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000792549	SCV001976465	likely pathogenic	Hypertrophic cardiomyopathy	2021-09-27	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.1012G>A (p.Val338Met) variant in MYH7 has been identified in at least 11 individuals with HCM (PS4_Moderate; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ambry, pers. comm.; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.), and at least in a presumably unaffected individual (<40 years old) with a family history of HCM (Valente 2013 PMID: 23690394; Captur 2014 PMID:25228707). This variant segregated with disease in 6 affected relatives with HCM from 3 families (PP1_Moderate, GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1_Moderate; PM2, PM1.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000792549	SCV000199244	likely pathogenic	Hypertrophic cardiomyopathy	2014-11-20	criteria provided, single submitter	clinical testing	The p.Val338Met variant in MYH7 has been identified by our laboratory in 2 indiv iduals with HCM and segregated with disease in 5 affected relatives from 1 famil y. Of note, affected individuals are reported to have varying ages of onset (age 3 - 50's). This variant was also identified in 2 teenagers with early signs of left ventricular wall thickening and in 3 asymptomatic obligate carriers. This v ariant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong evidence for or against an impac t to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Val338Met variant is likely pathogeni c.
GeneDx	RCV000158778	SCV000208713	likely pathogenic	not provided	2018-10-09	criteria provided, single submitter	clinical testing	The V338M likely pathogenic variant in the MYH7 gene has been reported in association with cardiomyopathy (Valente et al., 2013; Captur et al., 2014; Walsh et al., 2017). This variant has also been classified as a likely pathogenic variant and reported to segregate with disease in multiple members from one family by another clinical laboratory in ClinVar (SCV000199244.4; Landrum et al., 2016). The V338M variant is not observed in large population cohorts (Lek et al., 2016). A missense variant in the same residue (V338A) has been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue of the protein. Furthermore, the V338M variant is located in the myosin motor domain, a region enriched with missense variants reported in association with cardiomyopathy (Kelly et al., 2018). However, the V338M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, V338M in the MYH7 gene is interpreted as a likely pathogenic variant.
Invitae	RCV000792549	SCV000931853	pathogenic	Hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 338 of the MYH7 protein (p.Val338Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23690394, 27247418, 27532257, 32746448; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164381). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002345472	SCV002620615	likely pathogenic	Cardiovascular phenotype	2021-07-12	criteria provided, single submitter	clinical testing	The p.V338M variant (also known as c.1012G>A), located in coding exon 10 of the MYH7 gene, results from a G to A substitution at nucleotide position 1012. The valine at codon 338 is replaced by methionine, an amino acid with highly similar properties. 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 alteration has been detected in several individuals from hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing, and has shown some segregation with disease (Ho CY et al. Circ Cardiovasc Imaging, 2013 May;6:415-22; Captur G et al. Circ Cardiovasc Imaging. 2014;7:863-71; Homburger JR et al. Proc Natl Acad Sci USA. 2016;113(24):6701-6; Walsh R et al. Genet Med. 2017;19(2):192-203; Chida A et al. Heart Vessels. 2017 Jun;32(6):700-707; Mademont-Soler I et al. PLoS One. 2017 Aug;12(8):e0181465). In addition, this alteration has been detected by an outside laboratory in two probands reported to have HCM, and was reported to segregate with disease in multiple affected individuals from one family (LMM pers. comm.). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158778	SCV000280291	likely pathogenic	not provided	2013-04-17	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val338Met (c.1012G>A) in MYH7. We have seen this variant in a family with HCM and it was present in multiple affected family members. The variant has been seen in a total of two unrelated HCM case (including the family in our center). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The valine at codon 338 is highly, though not completely, conserved across species; it is an isoleucine in platypus, chicken, and lizard. Neighboring amino acids are completely or highly conserved. We ere unable to find other variants reported in association with disease at this codon or nearby codons (+/- 5 positions). In total the variant has not been seen in ~6500 publicly available population datasets. There is no variation at codon 338 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of August 6th, 2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of August 6th, 2012). No published or laboratory control data is available.