ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4258C>T (p.Arg1420Trp)

gnomAD frequency: 0.00001  dbSNP: rs145213771
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000758078 SCV000564450 likely pathogenic Hypertrophic cardiomyopathy 2021-12-09 reviewed by expert panel curation The NM_000257.4(MYH7):c.4258C>T (p.Arg1420Trp) variant has been reported in >15 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease (PS4_Strong; Van Driest 2004 PMID: 15358028; Millat 2010 PMID: 20624503; Millat 2010 PMID: 20800588; Teirlinck 2012 PMID:23140321; Zou 2013 PMID:23283745; Berge 2014 PMID: 24111713; Ntusi 2016 PMID: 27841901; Homburger 2016 PMID: 27247418; Walsh 2017 PMID:27532257; Ho 2018 PMID: 30297972; Gene Dx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has also been identified in 0.0003% (FAF 95% CI; 2/113756) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4, PM2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000758078 SCV000059548 likely pathogenic Hypertrophic cardiomyopathy 2023-10-27 criteria provided, single submitter clinical testing The p.Arg1420Trp variant has been identified in at least 15 individuals with hypertrophic cardiomyopathy (HCM: Van Driest 2004 PMID: 15358028, Millat 2010 PMID: 20624503, Bortot 2011 PMID: 21817903, Zou 2013 PMID: 23283745, Berge 2014 PMID: 24111713, Ntusi 2016 PMID: 27841901, O'Hare 2020 PMID: 33190526, LMM data). It has also been identified in 0.003% (2/68046) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses are consistent with pathogenicity. Another variant involving this codon (p.Arg1420Gln) has been identified in individuals with HCM and is classified as likely pathogenic by this laboratory. Additionally, this variant was classified as likely pathogenic on Dec 15, 2016 by the ClinGen-approved Cardiomyopathy expert panel (Variation ID: 43003). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5_Supporting, PP3.
GeneDx RCV001703872 SCV000208581 likely pathogenic not provided 2023-06-14 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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: 23299917, 24055113, 25637381, 18555187, 23403236, 25961035, 23283745, 22958901, 23447461, 15358028, 27247418, 27532257, 24111713, 29169752, 28971120, 21817903, 23140321, 37217627, 32419263, 35065800, 34601892, AlloubaM2022[Preprint], 33087929, 33190526, 34542152, 27841901, 28640247, 30297972, 35653365, 29300372, 20624503, 20800588)
Color Diagnostics, LLC DBA Color Health RCV001185537 SCV001351780 likely pathogenic Cardiomyopathy 2023-01-09 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 1420 in the LMM 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 individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 20624503, 23140321, 23283745, 27532257, 30297972, 35653365; Kassem et al. 2017). A different variant occurring at the same codon, p.Arg1420Gln, is a likely pathogenic mutation (Clinvar variation ID: 43004), indicating that arginine at this position is important for MYH7 protein function. This variant has been identified in 2/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV000758078 SCV001554903 pathogenic Hypertrophic cardiomyopathy 2024-01-09 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 1420 of the MYH7 protein (p.Arg1420Trp). This variant is present in population databases (rs145213771, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15358028, 20800588, 23283745, 24111713, 27247418, 27532257, 27841901, 29300372, 33190526). ClinVar contains an entry for this variant (Variation ID: 43003). 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.Arg1420 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21817903, 26914223, 27247418; Invitae). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001185537 SCV002572220 likely pathogenic Cardiomyopathy 2022-08-22 criteria provided, single submitter clinical testing Variant summary: MYH7 c.4258C>T (p.Arg1420Trp) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-06 in 252916 control chromosomes (gnomAD and publication data). c.4258C>T has been reported in the literature in individuals affected with hypertrophic cardiomyopathy (VanDriest_2004, Millat_2010, Teirlinck_2012, Zou_2013, Berge_2013, Wang_2014, Ntusi_2016, Walsh_2017, Ko_2017, Ho_2018, OHare_2020). These data indicate that the variant is likely to be associated with disease. In addition, other missense variants at the same codon (R1420Q, R1420L) have been found in patients with hypertrophic cardiomyopathy in HGMD, indicating the arginine residue is critical for the protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely pathogenic (n=2), including ClinGen Cardiomyopathy Variant Curation Expert Panel classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002504880 SCV002796123 likely pathogenic Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy 2022-01-18 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001185537 SCV003838102 likely pathogenic Cardiomyopathy 2022-03-22 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001703872 SCV004010267 likely pathogenic not provided 2023-04-01 criteria provided, single submitter clinical testing MYH7: PM1, PM2, PM5, PP2, PP3, PS4:Supporting
Baylor Genetics RCV003333012 SCV004041176 pathogenic Dilated cardiomyopathy 1S 2023-02-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV003333013 SCV004041177 pathogenic MYH7-related skeletal myopathy 2023-02-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV003333014 SCV004041233 pathogenic Hypertrophic cardiomyopathy 1 2023-02-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV003333015 SCV004041298 pathogenic Myopathy, myosin storage, autosomal recessive 2023-02-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV003333016 SCV004041318 pathogenic Myosin storage myopathy 2023-02-21 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148697 SCV000190426 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research

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