ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln) (rs193922390)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000586653 SCV000740053 likely pathogenic Cardiovascular phenotype 2017-01-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Blueprint Genetics, RCV000030320 SCV000264097 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-04 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000199234 SCV000747336 likely pathogenic Hypertrophic cardiomyopathy 2017-01-01 criteria provided, single submitter clinical testing
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000199234 SCV000564455 likely pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.5135G>A (p.Arg1712Gln) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:24510615; PMID:23785128; Partners LMM ClinVar SCV000059603.5, Invitae ClinVar SCV000253686.5, and SHaRe consortium, PMID: 30297972). This variant segregated with disease in 4 affected individuals (PP1; Partners LMM ClinVar SCV000059603.5; GeneDx ClinVar SCV000208619.11). This variant has been identified in 1/66706 European chromosomes (PM2; http://exac.broadinstitute.org). 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 likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM2; PP1; PP3
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000199234 SCV000804895 likely pathogenic Hypertrophic cardiomyopathy 2016-11-29 no assertion criteria provided clinical testing
GeneDx RCV000223711 SCV000208619 pathogenic not provided 2018-11-16 criteria provided, single submitter clinical testing The R1712Q variant in the MYH7 gene has been reported previously in association with hypertrophic cardiomyopathy (HCM) (Morita et al., 2008; Xu et al., 2010; Pan et al., 2012; Miller et al., 2013; Kapplinger et al., 2014; Lopes et al., 2015). Furthermore, the R1712Q variant has been observed in multiple other unrelated individuals tested for HCM at GeneDx and was shown to co-segregate with cardiomyopathy in at least three families. The R1712Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, the R1712Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties and occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, a missense variant in the same residue (R1712W) has been reported in association with cardiomyopathy, supporting the functional importance of this residue of the protein (Hougs et al., 2005; Jensen et al., 2013; Hagen et al., 2013). In summary, R1712Q in the MYH7 gene is interpreted as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000030320 SCV000052987 likely pathogenic Primary familial hypertrophic cardiomyopathy 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000586653 SCV000696356 likely pathogenic Cardiovascular phenotype 2017-07-21 criteria provided, single submitter clinical testing Variant summary: The MYH7 c.5135G>A (p.Arg1712Gln) variant causes a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/122290 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYH7 variant 1/100 (0.0010005). This is further substantiated by an increased prevalence of this variant among reports of affected individuals compared to its prevalence in controls. Multiple affected individuals have been ascertained through publications classifying the variant as "disease-causing" (Helms__Circ_2016, Lopes_Heart_2015). Although some conflicting reports exist, namely, an affected individual that also carried a likely pathogenic TNN13 variant, p.Arg162Gln (Gruner_CCG_2011) and an affected individual reporting a lack of co-segregation (Patient 44, Mook_BMJ_2013), HCM has been established as having digenic inheritance, variable expressivity and reduced penetrance. Also phenocopies of cardiac disease resulting in the reported lack of co-segregation cannot be excluded. Therefore, these findings do not eliminate the pathogenicity of this variant. Furthermore, since its last evaluation, multiple reputable databases/clinical laboratories continue to classify the variant as "likely pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a likely pathogenic until functional studies demonstrating the impact of this variant on the mechanism and pathophysiology of HCM along with unequivoal co-segregation within large pedigrees are reported.
Invitae RCV000199234 SCV000253686 likely pathogenic Hypertrophic cardiomyopathy 2018-06-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1712 of the MYH7 protein (p.Arg1712Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs193922390, ExAC 0.001%). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 21511876, 23785128, 24510615, 27247418, 27532257, 28771489, Invitae). ClinVar contains an entry for this variant (Variation ID: 36642). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000030320 SCV000059603 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-10-26 criteria provided, single submitter clinical testing The p.Arg1712Gln variant in MYH7 has been reported in more than 15 individuals with HCM (Morita 2008, Gruner 2011, Mook 2013, Walsh 2016, 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), but did segregate with disease in one affected individual from another family (LMM data). This variant has been identified in 6/126404 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922390). This variant has been reported in ClinVar (Variation ID: 36642) as likely pathogenic by an expert panel. Arginine (Arg) at position 1712 is conserved in evolution and the change to glutamine (Gln) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg1712Gln variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PM2, PP3 (Richards 2015).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000030320 SCV000748025 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-05-19 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223711 SCV000280361 likely pathogenic not provided 2014-01-24 no assertion criteria provided clinical testing 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).

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