ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1324C>T (p.Arg442Cys) (rs148808089)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000464365 SCV000204222 likely pathogenic Hypertrophic cardiomyopathy 2019-08-30 criteria provided, single submitter clinical testing The p.Arg442Cys variant in MYH7 has been identified in at least 10 individuals with HCM (Laredo 2006, Olivotto 2008, Witjas-Paalberends 2013, Berge 2014, Homburger 2016, Walsh 2017, LMM data). It has also been identified in 6/282878 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #177897). Of note, 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). Another variant involving this codon, p.Arg442His, has also been identified in individuals with cardiomyopathy. 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: PS4_Moderate, PM1, PM2, PP3.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000464365 SCV000212635 likely pathogenic Hypertrophic cardiomyopathy 2019-01-10 criteria provided, single submitter research This MYH7 Arg442Cys variant has been previously reported in 8 unrelated HCM cases (Laredo et al., 2007; Olivotto et al., 2008; Berge & Leren, 2013; Walsh et al., 2017). Olivotto et al. (2008) indicated that this novel variant was tested for cosegregation in affected family members (5 affected relatives of a large Italian family are carriers of the variant; Olivotto I, unpublished data). We have identified this variant in 1 affected HCM individual (Hamilton-Craig et al., 2014; Ingles et al., 2017). The variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.000014. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. In silico tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. We have identified this variant in 1 affected HCM individual. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant is located in a mutational hotspot (PM1), is rare in the general population (PM2), has been reported in at least 9 probands (PS4_moderate), has shown to segregate in at least 1 HCM family (PP1_moderate) and multiple in silico tools predict that this variant is deleterious (PP3), therefore we classify this variant as 'likely pathogenic'.
Invitae RCV000464365 SCV000546259 likely pathogenic Hypertrophic cardiomyopathy 2019-10-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 442 of the MYH7 protein (p.Arg442Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs148808089, ExAC 0.001%). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 17125710, 28615295, 18533079, 23674513, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 177897). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg442 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 17019812), which suggests that this may be a clinically significant amino acid residue. 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). 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.
Ambry Genetics RCV000622007 SCV000740049 likely pathogenic Cardiovascular phenotype 2019-06-25 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Center for Human Genetics,University of Leuven RCV000464365 SCV000886780 likely pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770500 SCV000901945 likely pathogenic Cardiomyopathy 2015-11-12 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000786167 SCV000927256 pathogenic not provided 2017-05-10 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000786167 SCV001249811 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786167 SCV000924861 likely pathogenic not provided 2016-08-11 no assertion criteria provided provider interpretation p.Arg442Cys (c.1324C>T) in exon 13 of the MYH7 gene (NM_000257.2) (14:23898247G>A) We have seen this variant in an individual with HCM. Testing was done by Invitae. Given sufficient case data with moderate segregation we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Some functional data is available and the variant is sufficiently rare in available control populations. The variant has been seen in at least 8 unrelated cases of HCM (not including this patient's family). There is strong case data with moderate segregation data and one case of the variant being reported in a case of DCM with another pathogenic variant. The variant was reported by Laredo et al., 2007 in a woman with HCM. No segregation data was reported. Olivotto et al., 2008 in a patient with HCM. The authors noted that the variant segregated with the phenotype. No details were given in the publication, but personal communication reported in the Agnes Ginges ClinVar entry indicates that it was present in 5 affected family members. Witjas-Paalberends et al., 2013 reported the variant in a woman with HCM. Berge et al., 2014 reported 3 HCM probands with the variant. The variant is listed in ClinVar by LMM, classifed as a VUS. They report that they have seen it in one adult with HCM and 1 adult with DCM who carried a pathogenic variant in another gene. It is listed as pathogenic by Anges Ginges Centre for Molecular Cardiology and has been seen by that center in 1 person with HCM. An abstract by Belus et al., 2008 (http://hdl.handle.net/2158/968997) reported that the R442C variant accelerates cardiac myofibril tension generation and relaxation demonstrated previously in established pathogenic MYH7 variant R403Q. Per the Invitae report the arginine residue at codon 442 is highly conserved and there is a large physicochemical difference between arginine and cysteine. The variant was reported online in 1 of 60,705 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 8/11/2016). Specifically, the variant was observed in 1 of 33,370 non-Finnish European people. 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant was also reported in 2 of 2504 people in 1000 Genomes (as of 8/11/2016). Please note that there is an overlap between this population and ExAC. One person was noted to be from Great Britain and the other was noted to be from Vietnam.

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