ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1207C>T (p.Arg403Trp) (rs3218714)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000456661 SCV000564412 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.1207C>T (p.Arg403Trp) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy and segregated with disease in >20 affected family members (PS4 and PP1_Strong; PMID:1052196; PMID:7662452; PMID:7848420; PMID:8254035; PMID:8268932; PMID:12707239; PMID:12974739; PMID:15010274; PMID:15856146; PMID:17612745; PMID:20428263; PMID:21239446; PMID:26383716; Partners LMM ClinVar SCV000059358.5; AGCMC Sydney ClinVar SCV000212643.1; SHaRe consortium, PMID: 30297972). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.1208G>A p.Arg403Gln - Variation ID 14087). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_Strong; PM1; PM2; PM5; PP3
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000456661 SCV000059358 pathogenic Hypertrophic cardiomyopathy 2012-01-18 criteria provided, single submitter clinical testing The Arg403Trp variant (MYH7) has been identified in 9 individuals with HCM, segr egated with disease in >15 affected relatives across several families, and was a bsent in >400 control chromosomes (Moolman 1993, Dausse 1993, Posen 1995, Moolma n-Smook 1999, Perrot 2005). Therefore, this variant meets our criteria for patho genicity (http://pcpgm.partners.org/LMM) based upon segregation and absence from controls.
GeneDx RCV000158787 SCV000208722 pathogenic not provided 2018-01-18 criteria provided, single submitter clinical testing p.Arg403Trp (CGG>TGG): c.1207 C>T in exon 13 of the MYH7 gene (NM_000257.2). The Arg403Trp mutation in the MYH7 gene has been reported multiple times in association with HCM (Richard P et al., 2003; Keller D et al., 2004; Dausse E et al., 1993; Revera M et al., 2008). Published control studies report that the Arg403Trp mutation was absent from 200 healthy control individuals (Richard P et al., 2003). The Arg403Trp mutation was identified in a homozygous state in a 38 year-old male with left atrial dilation and who was the recipient of a heart transplant (Keller D et al., 2004). Family segregation studies of this mutation concluded that the presence of Arg403Trp in the heterozygous state resulted in a less severe form of cardiomyopathy, compared to another mutation reported in at the same codon (Arg403Leu) (Dausse E et al., 1993). Furthermore, functional studies suggest that the Arg403Trp mutation reduces both systolic and diastolic function and ATP utilization (Revera M et al., 2008). Mutations at this codon (Arg403Gln, Arg403Leu) and a neighboring codon (Val404Met, Val404Leu) have been reported in association with cardiomyopathy further supporting the functional importance of this residue and this region of the protein. The NHLBI ESP Exome Variant Server reports Arg403Trp was not observed in approximately 5,000 control samples from individuals of European and African American backgrounds indicating it is not a common benign variant in these populations. In summary, Arg403Trp in the MYH7 gene is interpreted to be a disease-causing mutation. The variant is found in HCM panel(s).
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000015158 SCV000212643 pathogenic Familial hypertrophic cardiomyopathy 1 2014-12-22 criteria provided, single submitter research This MYH7 Arg403Trp variant is well described in multiple unrelated HCM families (see references). There is strong evidence that the variant co-segregates with disease in several families. Specifically, Posen et al. (1995) presented a large HCM family where the MYH7 Arg403Trp variant was present in 14 clinically affected members. The clinical phenotype observed is variable and disease characteristics range from no hypertrophy to mild left ventricular hypertrophy and/or ECG abnormalities. In addition to being absent in study control cohorts, this variant is also absent in general population databases including 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Furthermore, arginine (Arg) at position 403 is highly conserved across distantly related species, and is a known mutational hotspot region (Dausse E, et al., 1993). We have identified this mutation in one HCM case (no familial segregation possible) in our cohort. Based on the supporting literature and strong evidence of segregation with disease, absence in control cohorts, we classify this MYH7 Arg403Trp variant as "pathogenic".
Invitae RCV000456661 SCV000546195 pathogenic Hypertrophic cardiomyopathy 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 403 of the MYH7 protein (p.Arg403Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with familial hypertrophic cardiomyopathy (HCM) in multiple independent families (PMID: 8254035, 18029407). ClinVar contains an entry for this variant (Variation ID: 14102). A different missense substitution at this codon (p.Arg403Gln) has been determined to be pathogenic (PMID: 12975413, 1638703, 1975517, 23751935). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change (p.Arg403Trp) alters the enzymatic and mechanical properties of the MYH7 protein in cardiac muscle (PMID: 10882745, 15010274). In summary, this variant is a rare missense change that has been shown to affect protein function and segregates with disease. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515361 SCV000611214 pathogenic Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; Myopathy, distal, 1; MYH7-related late-onset scapuloperoneal muscular dystrophy 2017-05-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621657 SCV000740195 pathogenic Cardiovascular phenotype 2017-07-26 criteria provided, single submitter clinical testing Strong segregation with disease (lod >3 = >10 meioses);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000015158 SCV000840022 pathogenic Familial hypertrophic cardiomyopathy 1 2018-02-05 criteria provided, single submitter clinical testing This c.1207C>T (p. Arg403Trp) variant in the MYH7 gene has been reported in several unrelated patients with hypertrophic cardiomyopathy (HCM) and was shown to segregate with disease in the reported families (PMID8254035,7662452,.15010274, 17207239, and 18029407). In addition, two different missense variant substitutions affecting the same amino acid position, pArg403Gln and p.Arg403Leu, have been reported in additional patients with HCM (PMID12975413, 1638703, 1975517, 23751935,8254035, 17207239). This variant is highly conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 predict this p. Arg403Trp change to be deleterious. This c.1207C>T (p. Arg403Trp ) variant in the MYH7 gene is thus classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000158787 SCV001249813 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170740 SCV001333343 pathogenic Cardiomyopathy 2018-01-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001170740 SCV001363322 pathogenic Cardiomyopathy 2019-12-24 criteria provided, single submitter clinical testing Variant summary: MYH7 c.1207C>T (p.Arg403Trp) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes (gnomAD). c.1207C>T has been reported in the literature in multiple individuals affected with Cardiomyopathy (e.g. Dausse_1993, Yamashita_2000, Revera_2008, Burns_2017, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The variant has been shown to result in increased actin-sliding velocity and actin-related ATPase activity compared to controls, which may result in reduced myocardial efficiency in patients with the variant (Yamashita_2000, Keller_2004). Patients with the variant were also shown to have reduced systolic and diastolic function as assessed by clinical parameters when compared to non-carrier relatives (Revera_2008). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000015158 SCV000035415 pathogenic Familial hypertrophic cardiomyopathy 1 2013-10-09 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158787 SCV000280294 pathogenic not provided 2014-10-08 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg403Trp (c.1207C>T) in MYH7 Based on the data reviewed below we consider this variant very likely disease-associated. The variant has been seen in at least 11 unrelated cases of HCM with strong segregation data. The variant was first reported by Dausse et al (1993) in a kindred in which linkage studies pointed towards MYH7. Sequencing of exon 13 of MYH7 identified p.Arg403Trp and its presence was confirmed in 6 affected individuals. A subsequent publication that included some of the same authors reported two families that appear to be distinct from the initial report (Al-Mahdawi et al 1994). Three individuals in one family and two in the other had HCM and carried p.Arg403Trp. Moolman et al (1993) reported the variant segregating with disease in three affected family members. The same authors then report an additional large kindred with 13 affected individuals with the variant (Posen et al 1995). Richard et al (2003) reported the variant in one individual with HCM. The Seidman group reported on proband with the variant online (http://genepath.med.harvard.edu/~seidman/cg3/muts/MYH7_Arg403Trp.html). Perrot et al (2005) reported two affected family members with this variant. Keller et al (2004) reported a patient with severe HCM requiring transplant at 39 years of age who was homozygous for p.Arg403Trp and heterozygous for p.Val896Met in MYBPC3. Erdmann et al (2003) reported two affected family members with the variant. Haluza et al (2001) reported the variant in a 23yo male with HCM who was a compound heterozygote for this variant and p.Arg453His. Interestingly, p.Arg453His was de novo. He inherited p.Arg403Trp from his affected father. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 403 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Arg403Gln (very likely disease causing), p.Arg403Leu (likely disease causing)) and nearby codons (p.Arg404Leu, p.Arg404Met, p.Arg406Met, p.Arg407Val). Moolman et al (1993) noted that there is a CpG doublet at codon 403 which may likely makes it susceptible to mutation. In total the variant has not been seen in 5300 published controls and publicly available population datsets. There is no variation at codon 403 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5000 Caucasian and African American individuals (as of 1/14/2012). There is also no variation at this codon listed in 1000 genomes (as of 1/14/2012). p.Arg403Trp is listed in dbSNP, however this seems to refer to its role as an HCM-associated variant (rs3218714). The variant was not observed in the following published control samples: 50 (Al-Mahdawi et al 1994), 100 (Richard et al 2003), 54 (Moolman et al 1993), 96 (Perrot et al 2005).

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