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

gnomAD frequency: 0.00003  dbSNP: rs727503278

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2023-05-31	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); 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17947214, 19864899, 21839045, 25086479, 26914223, 27532257, 28615295, 28193612, 12974739, 23711808, 8981935, 3203908, 7909436, 17372140, 25666907, 8614836, 7883988, 20733148, 15322983, 12820698, 24093860, 15563892, 15358028, 18383048, 28771489, 22455086, 30588760, 31447099, 33309763, 32894683, 32344918, 33673806, 34542152, 34598319, 24510615, 35653365)
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 (http://gnomad.broadinstitute.org/) 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	pathogenic	Hypertrophic cardiomyopathy	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 143 of the MYH7 protein (p.Arg143Trp). This variant is present in population databases (rs727503278, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12974739, 23711808, 25086479, 27532257, 28408708, 28615295, 28771489, 30588760). ClinVar contains an entry for this variant (Variation ID: 164401). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg143 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15358028, 15563892, 21252143, 22765922, 24093860). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as 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
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798475	SCV002042680	likely pathogenic	Cardiomyopathy	2021-04-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001798475	SCV002052422	likely pathogenic	Cardiomyopathy	2022-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 143 of the myosin head/motor (S1) domain of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12974739, 25086479, 26914223, 27532257, 28408708, 28193612, 30588760, 32344918, 33495596, 33495597, 34598319; ClinVar SCV000199274.4), as well as in six individuals affected with or suspected of having hypertrophic cardiomyopathy (PMID: 24510615). Four family members of these probands have been reported to be unaffected carriers (PMID: 30588760). This variant has also been identified in a case of fetal left ventricular noncompaction (PMID: 33309763). This variant has been identified in 7/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg143Gln (Clinvar variation ID 43006), is known to cause familial hypertrophic cardiomyopathy, suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Clinical Genetics Laboratory, Region Ostergotland	RCV002251737	SCV002522545	likely pathogenic	Hypertrophic cardiomyopathy 1	2019-05-27	criteria provided, single submitter	clinical testing	PS4, PM5, PP3
Ambry Genetics	RCV002326865	SCV002631604	likely pathogenic	Cardiovascular phenotype	2023-03-13	criteria provided, single submitter	clinical testing	The p.R143W variant (also known as c.427C>T), located in coding exon 3 of the MYH7 gene, results from a C to T substitution at nucleotide position 427. The arginine at codon 143 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported multiple times in hypertrophic cardiomyopathy (HCM) cohorts (e.g., Erdmann J et al. Clin. Genet. 2003;64:339-49; Chiou KR et al. J Cardiol. 2015;65:250-6; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61; Walsh R et al. Genet. Med. 2017;19:192-203). Two other alterations in the same codon, p.R143Q and p.R143G, have also been associated with HCM (Mohiddin SA et al. Genet. Test, 2003;7:21-7; Song L et al. Clin. Chim. Acta. 2005;351:209-16). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV002251737	SCV004809108	pathogenic	Hypertrophic cardiomyopathy 1	2024-02-15	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000197008	SCV005045732	likely pathogenic	Hypertrophic cardiomyopathy	2018-06-11	criteria provided, single submitter	clinical testing	The c.427C>T (p.Arg143Trp) variant of the MYH7 gene has been identified in numerous (>15) individuals with Hypertrophic Cardiomyopathy (HCM) (PMID:12974739, 25086479, 26914223, 28408708, 28193612, 23711808, 28615295, 24510615, 24093860, 22765922, 22455086, 15563892, 27532257). This variant has also been reported in compound heterozygous status with a truncating variant (p.Arg1530*) in an individual with fatal dilated cardiomyopathy. In the same study, this variant was found in one individual with HCM and in a parent with mild septum hypertrophy of this individual , as well as in another individual with HCM and in the two asymptomatic siblings (67 and 70 yeas old, respectively) of this individual, suggesting incomplete penetrance (PMID: 30588760). In silico computational prediction suggests that the p.Arg143Trp variant may have deleterious effect on the protein function (REVEL score: 0.892). This variant is found to be rare (0.00002784) in the general population database (gnomAD). Another amino acid substitution at the same location (p.Arg143Gln) has been interpreted as likely pathogenic by the ClinGen Cardiomyopathy Variant Curation expert panel (ClinVar ID: 43006). Therefore, the c.427C>T (p.Arg143Trp) variant in the MYH7 gene is classified as likely pathogenic.
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; http://gnomad.broadinstitute.org/), 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.