ClinVar Genomic variation as it relates to human health

The NM_000257.4:c.2710C>T (p.Arg904Cys) variant in MYH7 has been identified in 4 individuals with DCM in the literature (1 of whom also had LVNC; van Spaendonck-Zwarts 2013 PMID:23349452; van der Zwaag 2011 PMID:20573160; Walsh 2017 PMID:27532257; Miller 2017 PMID29212898) and 3 individuals with LVNC (2 of which were pediatric; Yang 2014 PMID:25326635; Wang 2017 PMID:28855170; van Waning 2018 PMID:29447731). This variant was identified in 8 individuals with DCM and 1 proband with LVNC by clinical laboratories (GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers comm.). Only probands with DCM are counted towards PS4 (n=12; PS4_Moderate). This variant segregated with DCM in 15 affected individuals from 4 families (PP1_Strong; van der Zwaag 2011 PMID:20573160; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.) and was assumed de novo in 1 of the above cases (PM6; GeneDx pers. comm.). This variant has been identified in 0.010% (1/10080) of Ashkenazi Jewish chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but was absent from all other populations. A different pathogenic missense variant has been previously identified at this codon, which indicates that this residue may be critical to the function of the protein (PM5; c.2711G>A p.Arg904His - Variation ID 42926). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1_Strong, PM6, PM2, PM5, PP3.

MYH7 VCEP: PS4_Moderate, PM2_Supporting, PM5, PM6, PP1_Strong, PP3

The p.Arg904Cys variant in MYH7 has been identified in at least 4 individuals wi th DCM and segregated with disease in 11 affected relatives from 2 families (van der Zwaag 2011; Miller 2017; LMM data). It has also been identified in 1/9850 o f Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs727503253). Arginine (Arg) at position 904 is highly conserved in mammals and across evolutionarily distant species and the change to cysteine (Cys) was predicted to be pathogenic using a computational t ool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Of note, this variant li es 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, this variant meets criteria to be classified as pathogenic fo r dilated cardiomyopathy in an autosomal dominant manner based upon segregation studies, low frequency in controls, and predicted functional impact. ACMG/AMP Cr iteria applied: PP1_Strong; PM1; PM2; PP3; PS4_Supporting.

The c.2710C>T variant in the MYH7 gene changes the arginine to a cysteine at codon 904 in the resultant protein (p.Arg904Cys). This codon lies within an important functional domain of MYH7 (amino acids 181-937). It is an evolutionarily conserved location and in-silico tools predict this change to be damaging. This particular variant has been reported in multiple individuals with dilated cardiomyopathy and segregates within families (PMID: 27532257, 20573160). In addition, a different missense substitution at this same codon (p.Arg904His) is considered pathogenic. It is an extremely rare variant having been seen in 1/251442 (0.000398%) individuals in gnomAD. According to ClinGen's Inherited Cardiomyopathy Expert Panel guidelines for interpretation of MYH7 (PMID: 29300372), this variant is considered pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 904 of the MYH7 protein (p.Arg904Cys). This variant is present in population databases (rs727503253, gnomAD 0.01%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20573160, 23349452, 28855170, 29212898, 29447731; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164316). 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%. This variant disrupts the p.Arg904 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21750094, 22464770, 25448463; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The p.R904C pathogenic mutation (also known as c.2710C>T), located in coding exon 21 of the MYH7 gene, results from a C to T substitution at nucleotide position 2710. The arginine at codon 904 is replaced by cysteine, an amino acid with highly dissimilar properties and is located in the head (motor) domain of the protein. This variant was reported to segregate with disease in a large, multi-generational family with multiple members diagnosed with dilated cardiomyopathy (DCM) (van der Zwaag PA et al. Clin. Genet., 2011 May;79:459-67). Additionally, this variant has been reported in various cohorts of individuals diagnosed with DCM or left ventricular non-compaction (LVNC), however clinical data was limited (Wang C et al. J Am Heart Assoc, 2017 Aug;6(9); Miller EM et al. Circ Cardiovasc Genet, 2017 Dec;10(6); van Waning JI et al. J. Am. Coll. Cardiol., 2018 02;71:711-722). An alternate amino acid substitution at this position, p.R409H, has been reported in individual(s) with dilated cardiomyopathy (Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92). In addition to the clinical data presented in the literature, this amino acid position is highly conserved in available vertebrate species. Furthermore, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established; however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous; however, a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is found within the head region, which is enriched with pathogenic missense variants (PMID: 29300372). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These alternative changes (p.(Arg904His), p.(Arg904Leu), p.(Arg904Pro)) have been reported multiple times as likely pathogenic or pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel, and has been observed in multiple individuals with either dilated cardiomyopathy or left ventricular noncompaction cardiomyopathy (ClinVar, PMID: 34935411). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign