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

gnomAD frequency: 0.00001  dbSNP: rs145213771

Total submissions: 17

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	2024-07-22	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, 32419263, 35065800, 34601892, AlloubaM2022[Preprint], 33087929, 33190526, 34542152, 27841901, 28640247, 30297972, 35653365, 29300372, 20624503, 37217627, 36264615, 37652022, 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.
Labcorp Genetics (formerly Invitae), Labcorp	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
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795952	SCV005416040	likely pathogenic	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Strong+PS4_Moderate
CSER _CC_NCGL, University of Washington	RCV000148697	SCV000190426	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Solve-RD Consortium	RCV003333016	SCV005091287	likely pathogenic	Myosin storage myopathy	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team