ClinVar Genomic variation as it relates to human health

The p.Arg671Cys variant in MYH7 has been reported in 8 individuals with HCM (Mohiddin 2003, Richard 2003, Wang 2014, Walsh 2017, LMM data). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM1, PM2, PS4_Moderate, PP3.

Segregated with HCM in one relative of a single proband tested at GeneDx and in two relatives in published literature (PMID: 34345284); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12820698, 27532257, 12707239, 21310275, 25132132, 30626765, 27885498, 36143288, 31941943, 31447099, 25611685, 34345284, 28606303, 38377203, 37652022, 37850193, 29300372, 32381727, 36693943)

The c.2011C>T (p.Arg671Cys) variant in the MYH7 gene has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID 12820698, 12707239, 25132132, 27532257) and is not observed in general population databases. This variant is located in the critical myosin head domain of MYH7 and is predicted to be damaging by multiple in silico algorithms. Therefore, this c.2011C>T (p.Arg671Cys) variant in the MYH7 gene is classified as likely pathogenic.

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 671 of the MYH7 protein (p.Arg671Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 12820698, 25132132, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 164350). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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). For these reasons, this variant has been classified as Pathogenic.

The c.2011C>T variant in MYH7 causes an amino acid substitution, which replaces arginine with cysteine at position 671. It has not been reported in control populations in the Genome Aggregation Database (gnomAD). It has been previously reported in at least 15 apparently unrelated individuals with hypertrophic cardiomyopathy (PMID 12707239, 12820698, 25132132, 27532257, 27885498, 34345284, 33769460, and others, ClinVar database; CHEO internal data). This variant was reported to segregate with disease in at least four families (PMID 27885498, 34345284, ClinVar database). It was also reported as de novo with unconfirmed parental relationship in an individual with cardiac hypertrophy (PMID 32381727). This variant is located within the head region (codons 181-937) of the Myosin-7 protein (NM_000257.2; NP_000248.2), where MYH7 pathogenic variants are significantly clustered (PMID 29300372). The Arg671 residue is highly conserved across evolutionarily distant species. In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function. This variant is listed in ClinVar (VCV000164350). Based on the above information, we categorize this variant as pathogenic.

The p.R671C pathogenic mutation (also known as c.2011C>T), located in coding exon 16 of the MYH7 gene, results from a C to T substitution at nucleotide position 2011. The arginine at codon 671 is replaced by cysteine, an amino acid with highly dissimilar 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 variant was identified in one or more individuals with features consistent with hypertrophic cardiomyopathy, including a de novo occurrence, and segregated with disease in at least one family (Mohiddin SA et al. Genet Test. 2003;7(1):21-7; Richard P et al. Circulation. 2003;107(17):2227-32; Wang J et al. Eur J Heart Fail. 2014; 16(9):950-7; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Chida A et al. Heart Vessels. 2017;32:700-707; Walsh R et al. Genet. Med. 2017;19:192-203, Zhao S et al. J. Med. Genet., 2020 May;0:1-7; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000164350, PMID:12707239). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:25132132). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.942>=0.6, 3CNET: 0.993>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: MYH7 c.2011C>T (p.Arg671Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 252082 control chromosomes. c.2011C>T has been reported in the literature in multiple individuals affected with Cardiomyopathy (e.g. Mohiddin_2003, Richard_2003, Wang_2014, Zhao_2021, Chida_2017, Walsh_2017). Additionally it was observed de novo patient (Zhao_2021) and in a family with Cardiomyopathy (Chida_2017). These data indicate that the variant is very 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: 27885498, 12820698, 12707239, 27532257, 25132132, 32381727). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=1) and pathogenic/likely pathogenic (n=7). Based on the evidence outlined above, the variant was classified as pathogenic.