Submissions for variant NM_000257.4(MYH7):c.1231G>A (p.Val411Ile)

gnomAD frequency: 0.00001  dbSNP: rs730880868

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158790	SCV000208725	uncertain significance	not provided	2024-05-17	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15858117, 12974739, 23785128, 27532257, 29121657, 25351510, 33495597, 20624503, 37121957, 34542152, 20800588, 35653365, 37652022, 22429680, 36264615, 23140321, 32481709, 32894683, 30847666, 12975413, 29300372)
Ambry Genetics	RCV000619862	SCV000740068	likely pathogenic	Cardiovascular phenotype	2024-04-17	criteria provided, single submitter	clinical testing	The p.V411I variant (also known as c.1231G>A), located in coding exon 11 of the MYH7 gene, results from a G to A substitution at nucleotide position 1231. The valine at codon 411 is replaced by isoleucine, 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 reported in individuals from multiple hypertrophic cardiomyopathy cohorts, though clinical details were limited for some cases (Erdmann J et al. Clin. Genet., 2003 Oct;64:339-49; Woo A et al. Heart, 2003 Oct;89:1179-85; Yu B et al. J. Clin. Pathol., 2005 May;58:479-85; Millat G et al. Eur J Med Genet 2010 Jul;53:261-7; Teirlinck CH et al. BMC Med. Genet., 2012 Nov;13:105; Mook OR et al. J Med Genet. 2013 Sep;50(9):614-26; Lopes LR et al. Heart, 2015 Feb;101:294-301; Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799). This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697577	SCV000826197	pathogenic	Hypertrophic cardiomyopathy	2024-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 411 of the MYH7 protein (p.Val411Ile). This variant is present in population databases (rs730880868, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12974739, 12975413, 20800588, 22429680, 23785128, 27532257, 29121657, 30847666, 32894683). ClinVar contains an entry for this variant (Variation ID: 181339). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170739	SCV001333342	likely pathogenic	Cardiomyopathy	2022-08-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170739	SCV001346795	likely pathogenic	Cardiomyopathy	2023-11-06	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 411 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 12974739, 12975413, 20624503, 20800588, 22429680, 23785128, 25351510, 27532257, 29121657, 30847666, 32481709, 32731933, 32894683, 33495597, 37121957). In two families, this variant has been reported to segregate with disease in affected individuals (PMID: 15858117, 23140321). This variant has been identified in 6/282874 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000697577	SCV004830240	likely pathogenic	Hypertrophic cardiomyopathy	2023-08-17	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 411 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 12974739, 12975413, 20624503, 20800588, 22429680, 23785128, 25351510, 27532257, 29121657, 30847666, 32481709, 32731933, 32894683, 33495597). In two families, this variant has been reported to segregate with disease in affected individuals (PMID: 15858117, 23140321). This variant has been identified in 6/282874 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Institute of Immunology and Genetics Kaiserslautern	RCV004771465	SCV005382194	likely pathogenic	Hypertrophic cardiomyopathy 1	2024-09-20	criteria provided, single submitter	clinical testing	ACMG Criteria: PM1, PM2_P, PS4, PP3, PP5; Variant was found in a heterozygous state
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001170739	SCV005726035	likely pathogenic	Cardiomyopathy	2024-11-22	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.1231G>A (p.Val411Ile) results in a conservative amino acid change located in the Myosin Large ATPases domain (IPR001609) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251480 control chromosomes. c.1231G>A has been reported in the literature in individuals affected with Cardiomyopathy (example,Erdmann_2003, Teirlinck_2012). In one patient with Cardiomyopathy, the variant was also reported at a compound heterozygous state with Likely pathogenic p.Arg869His (Magri_2020). The variant was also reported in multiple studies of Cardiomyopathy, without primary information (example, PMID 37652022, 29121657). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12974739, 32481709, 23140321). ClinVar contains an entry for this variant (Variation ID: 181339). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Clinical Genetics, Academic Medical Center	RCV000158790	SCV001921917	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000158790	SCV001957967	likely pathogenic	not provided		no assertion criteria provided	clinical testing