ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154549 SCV000204222 uncertain significance not specified 2014-01-07 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg442Cys v ariant in MYH7 has been reported in 1 individual with HCM (Laredo 2006) and has also been identified in 1/178 British chromosomes by the 1000 Genome Project (db SNP rs148808089). In addition, this variant has now been identified by our labor atory in 2 Caucasian individuals with cardiomyopathy (1 adult with HCM and 1 adu lt with DCM, who carried a pathogenic variant in another gene). Arginine (Arg) a t position 442 is highly conserved in evolution and the change to cysteine (Cys) 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 these data support that this variant may be pathogenic, additional studies are needed to fully assess its cl inical significance.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000162335 SCV000212635 pathogenic Familial hypertrophic cardiomyopathy 1 2014-12-09 criteria provided, single submitter research This MYH7 Arg442Cys variant has not frequently been reported in the literature. The variant has been reported in 5 unrelated HCM cases (Laredo R, et al., 2007; Olivotto I, et al., 2008; Berge KE & Leren TP, 2013). Limited details about family history and segregation analyses were provided. Olivotto I, 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in affected family members (5 affected relatives of a large Italian family are carriers of the variant; Olivotto I, unpublished data). Interestingly, a variant at the same position resulting in a different amino acid change, Arg442His, has been identified to cause DCM and congestive heart failure at a very early age (Kamisago M, et al., 2006). The Arginine 442 position is highly conserved in evolutionarily distant species. Missense variants at this site are low in frequency - Arg442Cys variant is observed in the 1000 genomes project (MAF=0.0004), and occurs as a singleton event (MAF=0.000008132) in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). The computational tool SIFT predicts this amino acid change to be "deleterious", and a tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts the variant to be disease-causing. We have identified this variant in 1 affected HCM individual. In summary, based on the low frequency occurrence of the variant, available literature, and familial segregation data, we classify this variant as "pathogenic".
Invitae RCV000464365 SCV000546259 likely pathogenic Hypertrophic cardiomyopathy 2018-01-18 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 reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 17125710, 18533079, 23674513, 24111713, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 177897). 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, this variant is rare in population databases, has been observed in multiple unrelated individuals with hypertrophic cardiomyopathy, and is predicted to have a deleterious effect. In the absence of confirmed functional or segregation data, at this time this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000622007 SCV000740049 likely pathogenic Cardiovascular phenotype 2016-10-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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
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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