Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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 |
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, |
RCV001170739 | SCV001333342 | likely pathogenic | Cardiomyopathy | 2022-08-16 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
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, |
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, |
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, |
RCV000158790 | SCV001921917 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000158790 | SCV001957967 | likely pathogenic | not provided | no assertion criteria provided | clinical testing |