ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.611G>A (p.Arg204His) (rs397516260)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000543200 SCV000059642 likely pathogenic Hypertrophic cardiomyopathy 2019-05-22 criteria provided, single submitter clinical testing The p.Arg204His variant has been observed in >15 probands with hypertrophic cardiomyopathy and segregated with disease in at least 1 affected family member (Furqan 2017). Two of the affected individuals carried additional variants that may have also contributed to the their phenotypes (Furqan 2017). This variant has been reported in ClinVar (Variation ID 43095). It has also been identified in 5/282888 chromosomes in gnomAD (https://gnomad.broadinstitute.org). This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. 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 hypertrophic cardiomyopathy. ACMG/AMP criteria applied: PS4, PM1, PM2.
GeneDx RCV000035990 SCV000208684 uncertain significance not specified 2017-05-02 criteria provided, single submitter clinical testing The R204H variant has been previously reported in multiple individuals in association with HCM (Richard et al., 2003; Funada et al., 2010; Pan et al., 2012; Meyer et al., 2013; Berge et al., 2014; Su et al., 2014; Homburger et al., 2016; Ntusi et al., 2016; Walsh et al., 2017). The R204H variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is classified as a variant of uncertain significance in ClinVar by another clinical laboratory, where it has been observed in three adults with HCM and one adult with left ventricular hypertrophy, and three of these four adults reportedly also harbored other pathogenic variants (ClinVar SCV000059642.4; Landrum et al., 2016). Additionally, this variant has been observed both independently, and in conjunction with additional cardiogenetic variants, in several individuals referred for cardiomyopathy genetic testing at GeneDx, and was found to segregate with HCM in two affected relatives from two unrelated families observed at GeneDx. However, segregation data for this variant are limited as no segregation studies were described for the previously published cases, and no informative segregation data are available for the remaining cases observed at GeneDx due to the lack of clinical information provided and/or insufficient participation by informative family members. This substitution occurs at a position that is conserved in mammals, R204H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, although missense variants at the same residue (R204C, R204L) have been reported in the Human Gene Mutation Database in association with HCM (Homburger et al., 2016; Walsh et al., 2017), the clinical significance of these variants also remains to be definitely determined. Finally, while this variant has been reported in several individuals in association with HCM, both larger segregation studies and functional evidence are needed to further clarify the role of this variant in disease. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000543200 SCV000623754 pathogenic Hypertrophic cardiomyopathy 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 204 of the MYH7 protein (p.Arg204His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 27247418, 24111713, 27841901, 23816408, 24865491, 27532257). ClinVar contains an entry for this variant (Variation ID: 43095). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This missense change is located in a region of the MYH7 protein between codons 181 and 937 that encodes the majority of the myosin head domain and where a significant number of previously reported MYH7 missense mutations are found (PMID: 27532257). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170746 SCV001333351 uncertain significance Cardiomyopathy 2018-01-30 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256696 SCV001433097 likely pathogenic Familial hypertrophic cardiomyopathy 1 2020-01-06 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223767 SCV000280373 likely pathogenic not provided 2014-09-24 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. Review of data on p.Arg204His in MYH7 Summary: -Seen in at least 20 presumably unrelated cases of HCM (5 published, 15 unpublished). -3 of 20 cases who had sequencing of at least MYH7 and MYBPC3 had another sarcomere variant: -----Late 50s female with HCM and fhx of CHF and sudden death, carried another MYH7 variant (classified as likely pathogenic by LMM) -----Late 30s female with HCM and fhx of sudden death, carried an MYBPC3 variant (frameshift variant, LMM classified as pathogenic) -----Woman diagnosed at 72yo with LVWT 15 mm and an MYL2 variant (GeneDx classifies as variant of uncertain significance) -3 of 20 cases had an additional variant in a non-sarcomere gene: -----A 53yo male with LVWT 20 mm and a daughter with HCM carried a variant of uncertain significance in MTTG -----A patient carried a variant in MuRF2 that the authors hypothesize is a modifier -----Late 40s female with LVH and NSVT and fhx of “possible HCM/enlarged heart and sudden death, and carried a variant in PKP2 (-1 splice variant, LMM classified as likely pathogenic) -There is weak segregation data. In at least one family an additional affected relative carried this variant. -The variant was not observed in a total of ~61,161 individuals from published controls and publicly available datasets that were not selected for HCM. Published cases: Richard et al. (2003) reported this variant in one out of 197 patients diagnosed with HCM that were cared for in Paris, France, who underwent analysis of the MYH7, MYBPC3, MYL2, MYL3, TNNI3, and TNNT2 genes. This case is most likely redundant with a later report by the same group (Gandjbakhch et al. 2010). Meyer et al. (2013) reported this variant in one out of 8 patients diagnosed with HCM that were cared for in Marburg, Germany, who underwent analysis of MYH7 and MYBPC3. No other phenotypic information was reported in the paper. Berge et al. (2014) reported this variant in one out of 696 patients diagnosed with HCM that were cared for in Norway, who underwent analysis of the MYH7, MYBPC3, TNNI3, TNNT2, MYL2, and MYL3 genes. No other phenotypic information was reported in the paper. Su et al. (2014) reported this variant in 2 patients diagnosed with HCM that were cared for in Beijing, China, who underwent analysis of MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1, MuRF1, MuRF2, and MuRF3 genes. One of the two patients carries a second variant in MuRF2 gene (c.1516A>T; p.T506S). Authors propose that rare variants in MuRF2 genes increase the risk of development of HCM and lead to more severe disease phenotypes, and thus may act as modifiers of the disease. This variant substitutes a polar, positively charged amino acid (Arg) with a polar, positively charged amino acid (His). In silico analysis with PolyPhen-2 predicts the variant to be “possibly damaging” and SIFT predicts the variant to be “deleterious.” The Arginine at codon 204 is moderately conserved across species, as are neighboring amino acids. It is highly conserved among mammals. Other variants have been reported in association with disease at this codon (c.610C>T (p.Arg204Cys) with classification as pathogenic by GeneDx in ClinVar, no other submitters; c.611G>T (p.Arg204Leu) with conflicting classifications in ClinVar) and nearby codons (p.Ala199Val; p.Ile201Thr (Villard, 2005); p.Lys207Gln (Mohiddin, 2003)). The variant was not observed in ~61,113 individuals from published controls and publicly available datasets that approximate the general population. This includes ~60,706 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of April 22nd, 2015). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population; others were enriched for common cardiovascular disease. They were not selected for HCM and in some cases Mendelian heart disease was excluded. This variant is currently listed in dbSNP: rs397516260. The variant was not observed in the following published control samples: Richard (2003) did not report this variant in 100 control individuals, Su (2014) did not report this variant in 307 control individuals.

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