ClinVar Genomic variation as it relates to human health

The NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln) variant has been reported in >30 individuals with HCM (PS4; Miller 2013 PMID: 23054336; Mook 2013 PMID: 23785128; Glotov 2015 PMID: 25892673; Lopes 2015 PMID: 25351510; Helms 2016 PMID: 27688314; Mademont-Soler 2017 PMID: 28771489; Weissler-Snir 2017 PMID: 28193612; van Velzen 2017 PMID: 2879411; van Lint 2019 PMID: 30847666; Tran Vu 2019 PMID: 31308319; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; LMM pers. comm.; Mayo pers. comm.; OMGL pers. comm.). This variant segregated with disease in >15 affected relatives with HCM in at least 9 families (PP1_strong; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has also been identified in 0.002% (FAF 95% CI; 6/128842) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4, PP1_strong, PM2.

_x000D_ Criteria applied: PS4_MOD, PM5, PM2_SUP, PP3

Not observed at a 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: 30531895, 34542152, 21310275, 21511876, 15483641, 18403758, 25351510, 23074333, 23785128, 24510615, 24835277, 23054336, 27247418, 27688314, 27532257, 28193612, 28241245, 20298698, 29661763, 30022097, 31737537, 30847666, 31447099, 28771489, 29300372, 32894683, 33087929, 34352619, 33673806, 35626289, 35653365)

Variant summary: MYH7 c.5135G>A (p.Arg1712Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251880 control chromosomes. c.5135G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Lopes_2015, Miller_2013, Morita_2008, Helms_2016, Sepp_2022, Pollman_2021). Additionally, another change at the same amino acid c.5134C>T (p.Arg1712Trp) has been classified as pathogenic/likely pathogenic in ClinVar by multiple submitters supporting the functional importance of this residue of the protein. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 18403758, 20298698, 23074333, 24835277, 27247418, 27532257, 27688314, 28193612, 25892673, 21511876, 33673806, 24510615, 25351510, 23054336, 23785128, 35626289, 34830538). 21 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

MYH7: PP1:Strong, PM5, PS4:Moderate, PP2, PP3

The rare missense variant, c.5135G>A (p.Arg1712Gln) , in the MYH7 gene (seen 6 times in gnomAD) has been observed in at least 10 unrelated probands with hypertrophic cardiomyopathy with evidence of segregation with disease in some families (PMID 18403758, 21511876, 29300372, 23074333, 23785128, 24510615, 27247418). Based upon the above evidence, this c.5135G>A (p.Arg1712Gln) variant in MYH7 is classified as likely pathogenic.

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 4-LIKELY 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). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 29300372). (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a glutamine (exon 35). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (6 heterozygotes, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (Myosin tail; PDB). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. A comparable missense variant resulting in a major amino acid change to a tryptophan, has been previously reported in HCM patients (ClinVar, PMID: 15483641). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple HCM patients (ClinVar, VCGS, PMID: 29300372, 24510615, 23785128). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

This missense variant replaces arginine with glutamine at codon 1712 in the LMM domain of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 30 individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 21511876, 23785128, 24510615, 27247418, 27532257, 28771489, 30297972, 31308319, 33495596, 33495597, 34352619, 34542152, 35026164, 35176171). It has been shown that this variant segregates with disease in over 20 affected relatives across at least 10 families (PMID: 37488328; ClinVar SCV000564455.5). This variant has been shown to have both age- and sex-dependent penetrance (PMID: 37488328). This variant has been identified in 6/282354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg1712Trp, is considered to be disease-causing (Clinvar variation ID: 14118), indicating that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Pathogenic.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1712 of the MYH7 protein (p.Arg1712Gln). This variant is present in population databases (rs193922390, gnomAD 0.005%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18403758, 21511876, 23785128, 24510615, 27247418, 27532257, 31308319, 32894683). ClinVar contains an entry for this variant (Variation ID: 36642). 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.Arg1712 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15483641). 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.Arg1712Gln variant in MYH7 has been reported in more than 15 individuals with hypertrophic cardiomyopathy (HCM; Morita 2008 PMID: 18403758, Gruner 2011 PMID: 21511876, Mook 2013 PMID: 23785128, Walsh 2016 PMID: 27532257, LMM data), including at least 1 individual with a likely disease-causing variant in another gene. This variant did not segregate with disease in one affected family member from one family (Mook 2013 PMID: 23785128), but did segregate in more than 15 affected individuals with HCM in at least 9 families (LMM internal data, GeneDx personal communication, Mayo Personal Communication, OMGL personal communication). This variant has been identified in 0.0045 (3/68048) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org, v.3.1.2). This variant has been classified as pathogenic on December 9, 2021 by the ClinGen Cardiomyopathy Variant Curation Expert Panel (Variation ID 36642). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. Criteria applied (Richards 2015): PS4, PP1_Strong, PM2_Supporting.

The p.R1712Q pathogenic mutation (also known as c.5135G>A), located in coding exon 33 of the MYH7 gene, results from a G to A substitution at nucleotide position 5135. The arginine at codon 1712 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (Morita H et al. N. Engl. J. Med. 2008; 358:1899-908; Gruner C et al. Circ Cardiovasc Genet 2011;4:288-95; Mook OR et al. J. Med. Genet., 2013;50:614-26; Tran Vu MT et al. Circ. J., 2019 Aug;83:1908-1916). One of those individuals also harbored an alteration in another sarcomere protein gene, but no information was provided about the alterations in other affected relatives in the family (Gruner C et al. Circ Cardiovasc Genet 2011;4:288-95). This variant was reported not to segregate with disease in a family in the literature (Mook OR et al. J. Med. Genet., 2013;50:614-26), and at least two clinical laboratories have observed segregation of this variant with HCM in multiple families (personal communications). In addition, this alteration has been described in HCM cohorts, although clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61; Lopes LR et al. Heart. 2015;101(4):294-301; Walsh R et al. Genet. Med. 2017;19:192-203). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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.Arg1712Gln (c.5135G>A) in the MYH7 gene. Given the data reviewed below, we consider it likely disease causing. This variant has been observed previously in at least 9 unrelated cases of HCM (not including this patient), with weak segregation. Per the ClinVar database, this variant has been observed in 17 individuals from 9 unrelated families (as of June 23, 2015). In 2005 Peng et al submitted the variant to the Harvard Cardiogenomics Sarcomere Mutation Database. Unfortunately no clinical or family data is provided online. GeneDx reports that the variant has been seen in three unrelated cases of HCM and in each case there was another affected first degree relative that also had the variant. This variant is currently present in dbSNP (rs193922390) from a single SNV submission by Corralagen, where they comment “HCM” (thus presumably, this represents another individual with HCM identified with this variant). This missense variant results in a non-conservative amino acid change with a positively charged hydrophilic Arginine replaced with a neutral, hydrophilic Glutamine. Arginine is highly conserved at this residue across several species. A different amino acid change at the same codon has been reported in two different Dutch families with HCM (p.Arg1712Trp) (Hougs et al 2005). This variant falls within the myosin tail domain (which spans residues 1068-1926)." We looked at the paper Mook et al. 2013, but the authors provide little detail about the variant not segregating with disease. In Table 4, they state that this variant was identified with a 70 yo with HCM, and in the notes section they state that it was seen in "9 Dutch index cases (one family no co-segregation in affected daughter)". We emailed the authors in Feb 2015 and have never heard back. In total the variant has not been seen in ~60,800 individuals from the general population. GeneDx notes that p.Arg1712Gln was not reported in 200 presumably healthy controls at of both Caucasian and African American ancestry. There is no variation at codon 1712 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,300 Caucasian and African American individuals (as of June 23, 2015). This variant is present in 1 individual in the ExAC database which contains exome data from 60,683 individuals of various ancestries (this 1 indiivdual is of European descent).