ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.427C>T (p.Arg143Trp) (rs727503278)

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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 RCV000197008 SCV000199274 likely pathogenic Hypertrophic cardiomyopathy 2020-10-05 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000505756 SCV000208665 likely pathogenic not provided 2020-10-02 criteria provided, single submitter clinical testing Observed in individuals with cardiomyopathy and/or sudden cardiac death and in unaffected relatives from three families, including one family in which the variant was identified in trans with another MYH7 variant (Hershkovitz et al., 2019); Reported in a 32 year-old male with a family history of sudden cardiac death, who also harbored a splice site variant in the TPM1 gene (Maron et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018) This variant is associated with the following publications: (PMID: 32344918, 31447099, 30588760, 22455086, 28771489, 18383048, 15358028, 15563892, 24093860, 12820698, 15322983, 20733148, 7883988, 17947214, 8614836, 25666907, 17372140, 7909436, 3203908, 8981935, 23711808, 12974739, 28193612, 28615295, 27532257, 26914223, 25086479, 21839045, 24510615, 19864899)
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000197008 SCV000223877 likely pathogenic Hypertrophic cardiomyopathy 2019-02-01 criteria provided, single submitter research This MYH7 Arg143Trp variant has previously been reported in HCM cohorts (Erdmann J et al., 2003; Van Driest SL et al., 2004; Maron BJ et al., 2011; Liu W et al., 2013; Kapplinger JD et al., 2014; Chiou KR et al., 2014; Mademont-Soler I et al., 2017; Walsh R et al., 2017), and has been been proven to segregate in one family (Mademont-Soler I et al., 2017). We have also identified this variant in one isolated HCM case (Ingles J et al., 2017). This variant is present in the Genome Aggregation Database ( at an allele frequency of 0.000028. Interestingly, a different rare variant at this position (Arg143Gln) has been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster and PolyPhen-2 predict this variant to be "deleterious". In summary, based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant this variant has been reported in more than 10 unrelated probands (PS4), is rare in the general population (PM2), segregates to affected individuals in one family (PP1) and in silico tools predict the variant is deleterious (PP3), therefore we classify this variant as 'likely pathogenic'.
Invitae RCV000197008 SCV000253685 likely pathogenic Hypertrophic cardiomyopathy 2018-08-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 143 of the MYH7 protein (p.Arg143Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs727503278, ExAC 0.01%). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12974739, 25086479, 28615295, 23711808, 28408708, 28771489, 27532257) and/or referred for HCM genetic testing (PMID: 24510615). ClinVar contains an entry for this variant (Variation ID: 164401). A different missense substitution at this codon (p.Arg143Gln) is reported to be deleterious (PMID: 11433818, 20075948, 24093860). This indicates that the arginine residue is important for MYH7 protein function. 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 RCV000623055 SCV000742437 likely pathogenic Inborn genetic diseases 2017-05-12 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000505756 SCV000928052 pathogenic not provided 2018-11-14 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845365 SCV000987421 likely pathogenic Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000505756 SCV000924866 likely pathogenic not provided 2017-10-16 no assertion criteria provided provider interpretation p.Arg143Trp (c.427C>T) in the MYH7 gene (NM_000257.3) chr14-23901923-G-A rs727503278 Seen in one patient with HCM in our center. Given the case data and an additional pathogenic variant at the same amino acid position, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Because of its frequency in gnomAD, it has been classified as likely pathogenic and not pathogenic. It should also be re-reviewed periodically given its frequency in gnomAD. The variant has been seen in at least 10 unrelated cases of HCM (not including this patient's family), 5 patients referred for HCM genetic testing, 1 patient with DCM (and an MYH7 loss of function variant in trans). The possibility of overlap of patients is minimal since most of the case reports are published from varying institutions, unless otherwise noted below. There is strong case data and modrate segregation data. Erdmann et al (2003) saw this variant in 1 patient with HCM. Patients recruited were either Turkish, Greek, Italian, or German. Liu et al (2013) reports one patient with this variant, but the c.DNA position is listed as c.533C>T. Kapplinger et al (2014) saw this variant in 6 cases of HCM, (either diagnosed with HCM at Mayo or referred for HCM genetic testing). Chiou et al (2014) reports the variant in 1 Taiwanese patient with HCM. Nomenclature for cDNA is c.533C>T as well. Walsh (2016) reports this variant in 2 patients with clinical diagnosis of HCM. Mademont-Soler (2017) reports this variant in 1 index pt with HCM. Authors note that three other affected family members tested positive, but do not provide degree of relation or other clinical details. Ingles et al (2017) considered this variant pathogenic and have seen this variant in an HCM patient at their center. Maron BJ, et al. (2012) reports this variant in a 32yo male with HCM and family history of SCD who also harbored a splice variant in TPM1. Murphy et al. (2016) identified in 1 patient with HCM recruited from Mayo. This might not be a unique case as patients in this study had genetic testing at clinical labs including Transgenomic (which would be redundant with Kapplinger et al) and LMM. LMM: - a patient with DCM who carried an MYH7 loss of function variant in trans (there is an emerging hypothesis that MYH7 variants may contribute to cardiomyopathy risk in a recessive fashion). -a patient with HCM In Homburger et al 2016, the residue is enriched in HCM cases vs. ExAC. Another variant at the same residue R143Q has been reported as pathogenic/likely pathogenic by 7 laboratories in ClinVar. This R143Q variant has not been seen at our center, nor did I perform a complete review based on the data in ClinVar. It is only present in 1 European individual in gnomAD. The R143W variant has been seen in 7 in 123,126 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD;, which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 2 of 8,624 East Asian individuals (MAF = 0.01160%), 4 of 55,850 European (NF) individuals (MAF = 0.003581%), and 1 of 15,391 South Asian individuals (MAF = 0.003249%). I checked the filtering allele frequency for this variant in ExAC and it passes the threshold for HCM.

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