Submissions for variant NM_000257.4(MYH7):c.2348G>A (p.Arg783His)

gnomAD frequency: 0.00002  dbSNP: rs397516142

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000157359	SCV000207097	likely pathogenic	Cardiomyopathy	2015-05-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000444026	SCV000513803	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18258667, 27532257, 24111713, 25351510, 27662471, 28831623, 29915097, 28606303, 31737537, 33673806, Farn2021[CaseReport], 35653365, 34542152, 35063694, 35626289, 35456187, 29300372, 30615648, 35534676, 34621001, 30775854)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001220856	SCV000539835	likely pathogenic	Hypertrophic cardiomyopathy	2019-12-09	criteria provided, single submitter	clinical testing	The p.Arg783His variant in MYH7 has been identified in at least 10 individuals with HCM (Berge 2014, Waldmuller 2008, Walsh 2016) and 1 individual with sudden cardiac death who also carried a frameshift variant in TTN (Shanks 2018). It has been reported in 4/129170 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in ClinVar (Variation ID: 180437). Of note, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In addition, several other variants involving this codon, p.Arg783Cys, p.Arg783Pro, and p.Arg783Gly, have also been identified in individuals with cardiomyopathy. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PS4_Moderate, PM5_Supporting, BP4.
Ambry Genetics	RCV000618642	SCV000740110	likely pathogenic	Cardiovascular phenotype	2023-02-27	criteria provided, single submitter	clinical testing	The p.R783H variant (also known as c.2348G>A), located in coding exon 19 of the MYH7 gene, results from a G to A substitution at nucleotide position 2348. The arginine at codon 783 is replaced by histidine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in numerous individual from hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing (Waldmüller S et al. Clin. Chem., 2008 Apr;54:682-7; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart, 2015 Feb;101:294-301; Jääskeläinen P et al. ESC Heart Fail. 2019 Apr;6(2):436-445; Marschall C et al. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298; Hathaway J et al. BMC Cardiovasc Disord. 2021 03;21(1):126; Ambry internal data). This variant has also been reported in a subject with restrictive cardiomyopathy whose son had HCM with restrictive features (Kostareva A et al. PLoS ONE., 2016 Sep;11(9):e0163362). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000444026	SCV001248600	likely pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	MYH7: PM1, PM2, PS4:Moderate
Invitae	RCV001220856	SCV001392868	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 783 of the MYH7 protein (p.Arg783His). This variant is present in population databases (rs397516142, gnomAD 0.004%). This missense change has been observed in individual(s) with Hypertrophic cardiomyopathy (PMID: 18258667, 24111713, 25351510, 27532257, 27662471, 33673806, 35626289; Invitae). ClinVar contains an entry for this variant (Variation ID: 180437). 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.Arg783 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21211974). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
3billion	RCV001808427	SCV002058663	pathogenic	Hypertrophic cardiomyopathy 1	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000180437, PMID:18258667, PS1_S). A different missense change at the same codon (p.Arg783Pro, p.Arg783Gly) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042895,VCV000164335, PMID:21211974, PMID:27247418, PM5_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000021, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
AiLife Diagnostics, AiLife Diagnostics	RCV000444026	SCV002501664	uncertain significance	not provided	2021-07-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455847	SCV003934392	uncertain significance	not specified	2023-05-05	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.2348G>A (p.Arg783His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2348G>A has been reported in the literature in individuals affected with Cardiomyopathy and some publications classified this variant as pathogenic or likely pathogenic, however strong evidence for causality such as co-segregation information was not specified (examples: Lopes_2013, Walsh_2017, Sahlin_2018, Shanks_2018, Marschall_2019, Hathaway_2021, Park_2022, Sepp_2022, and Stava_2022). In two of these cases authors reported evidence of TTN variants as co-occurrences where authors classified the TTN variant as likely pathogenic (example: Shanks_2018 and Zhu_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33673806, 31737537, 34542152, 35626289, 29915097, 35653365, 18258667, 27532257, 35063694, 25351510, 30615648). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=5) and VUS (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000444026	SCV004236710	uncertain significance	not provided	2023-03-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000157359	SCV004356921	likely pathogenic	Cardiomyopathy	2023-10-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 783 of the myosin head/motor (S1) domain of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18258667, 24111713, 27662471, 27532257, 30775854), and in 3 individuals suspected to be affected with hypertrophic cardiomyopathy (PMID: 33673806). It has also been reported in an individual affected with primary fibrotic atrial cardiomyopathy (PMID: 35063694), in a case of stillbirth (PMID: 30615648), and in an individual affected with sudden unexplained death (PMID: 29915097). A different variant affecting the same codon, p.Arg783Pro, is considered to be disease-causing (ClinVar variation ID: 42895), suggesting that arginine at this position is important for MYH7 protein function. This variant has been identified in 6/282860 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.