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 2018-09-12 criteria provided, single submitter clinical testing The p.Arg143Trp variant in MYH7 has been identified in at least 13 individuals w ith HCM, including one with a potential disease causing variant in another HCM g ene (Erdmann 2003, Maron 2012, Liu 2013, Kapplinger 2014, Chiou 2015, Murphy 201 6, Walsh 2016, LMM data). Additionally, the p.Arg143Trp variant has been identif ied in 1 child with DCM who also had another loss of function variant in the oth er copy of the MYH7 gene (LMM data). This variant has also been reported by othe r clinical laboratories in ClinVar (Variation ID: 8617) and has been identified in 2/17248 East Asian chromosomes and 4/111700 European chromosomes by the Genom e Aggregation Database (gnomAD,; dbSNP rs72750 3278). Computational prediction tools and conservation analysis suggest that the p.Arg143Trp variant may impact the protein. Additionally, another likely pathog enic variant (p.Arg143Gln) has been reported at this position, suggesting that c hanges to this amino acid residue (Arg) may not be tolerated. In summary, althou gh additional studies are required to fully establish its clinical significance, the p.Arg143Trp variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, P M2, PM5, PP3.
GeneDx RCV000505756 SCV000208665 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The R143W variant in the MYH7 gene has previously been reported in association with HCM (Erdmann et a., 2003; Liu et al., 2013; Chiou et al., 2014;Kapplinger et al., 2014). R143W was also 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). This variant has also beenobserved, both independently and in conjunction with additional cardiogenetic variants, in other unrelated individualsreferred for cardiomyopathy genetic testing at GeneDx. This variant has also been identified in a homozygous state in an unrelated individual of Asian descent. So far, segregation data is limited or absent for these individuals. In addition, this variant has been classified as both a variant of uncertain significance and a likely pathogenic variant byother clinical laboratories (ClinVar SCV000199274.3, SCV000253685.2; Landrum et al., 2016). The R143W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictorsand evolutionary conservation, support a deleterious effect. Furthermore, a different likely pathogenic missense variantaffecting the same residue (R143Q) has been reported multiple times in association with HCM (Song et al., 2005;Fokstuen et al., 2011; Coto et al., 2012; Curila et al., 2012; Lopes et al., 2015), however the pathogenicity of thisvariant remains to be definitely determined. Nevertheless, this variant is observed in 2/17248 (0.01%) alleles of EastAsian population cohorts and in 7/246252 (0.003%) alleles in the global population (Lek et al., 2016). In conclusion,additional evidence is needed to clarify pathogenicity, including informative segregation data and functional evidence.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000172887 SCV000223877 likely pathogenic Familial hypertrophic cardiomyopathy 1 2015-03-20 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). No strong evidence of segregation with disease phenotype have been published. However, Kapplinger et al. (2014) report this variant in 6 unrelated HCM cases and describe this MYH7 Arg143Trp variant to be nominally over represented in cases compared to control samples. We have identified this variant in one isolated HCM case (no familial segregation is possible). This variant is absent in the 1000 genomes project (, and present at a low frequency (MAF=0.00004942) in the Exome Aggregation Consortium dataset ( 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 predicts this variant to be "deleterious", but no prediction is called by PolyPhen-HCM. In summary, the identification of this variant in multiple unrelated individuals with the same phenotype and its extreme rarity/absence in controls suggest that MYH7 Arg143Trp is "likely pathogenic". Additional evidence is required to fully establish its pathogenic role.
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 uncertain significance Inborn genetic diseases 2017-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
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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