Submissions for variant NM_000257.4(MYH7):c.2011C>T (p.Arg671Cys)

dbSNP: rs727503263

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000461116	SCV000199213	likely pathogenic	Hypertrophic cardiomyopathy	2019-08-16	criteria provided, single submitter	clinical testing	The p.Arg671Cys variant in MYH7 has been reported in 8 individuals with HCM (Mohiddin 2003, Richard 2003, Wang 2014, Walsh 2017, LMM data). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). 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: PM1, PM2, PS4_Moderate, PP3.
GeneDx	RCV000766426	SCV000208758	likely pathogenic	not provided	2023-07-14	criteria provided, single submitter	clinical testing	Segregated with HCM in one relative of a single proband tested at GeneDx and in two relatives in published literature (Yu et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12820698, 27532257, 12707239, 21310275, 25132132, 30626765, 27885498, 32381727, 36143288, 31941943, 31447099, 25611685, 34345284, 28606303, 29300372)
Invitae	RCV000461116	SCV000546221	pathogenic	Hypertrophic cardiomyopathy	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 671 of the MYH7 protein (p.Arg671Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 12820698, 25132132, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 164350). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000620591	SCV000737368	pathogenic	Cardiovascular phenotype	2022-04-25	criteria provided, single submitter	clinical testing	The p.R671C pathogenic mutation (also known as c.2011C>T), located in coding exon 16 of the MYH7 gene, results from a C to T substitution at nucleotide position 2011. The arginine at codon 671 is replaced by cysteine, an amino acid with highly dissimilar properties. The altered codon is located in a region of the myosin head domain shown to be enriched for pathogenic missense mutations in hypertrophic cardiomyopathy (HCM) (Walsh R et al. Genet. Med. 2017;19:192-203). This alteration has been detected in multiple individuals diagnosed with HCM (Mohiddin SA et al. Genet Test. 2003;7(1):21-7; Richard P et al. Circulation. 2003;107(17):2227-32; Wang J et al. Eur J Heart Fail. 2014; 16(9):950-7; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med. 2017;19:192-203), and was reported as a de novo mutation in one patient with left ventricular hypertrophy (Zhao S et al. J. Med. Genet., 2020 May;0:1-7). In addition, this mutation co-segregated with HCM in a family reported in the literature (Chida A et al. Heart Vessels. 2017;32:700-707), as well as in one family in our laboratory (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770495	SCV000901940	uncertain significance	Cardiomyopathy	2015-10-06	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197245	SCV001367882	likely pathogenic	Congenital myopathy with fiber type disproportion	2019-07-04	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258093	SCV001434937	likely pathogenic	Hypertrophic cardiomyopathy 1	2019-03-15	criteria provided, single submitter	clinical testing	The c.2011C>T (p.Arg671Cys) variant in the MYH7 gene has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID 12820698, 12707239, 25132132, 27532257) and is not observed in general population databases. This variant is located in the critical myosin head domain of MYH7 and is predicted to be damaging by multiple in silico algorithms. Therefore, this c.2011C>T (p.Arg671Cys) variant in the MYH7 gene is classified as likely pathogenic.
3billion	RCV001258093	SCV002318667	pathogenic	Hypertrophic cardiomyopathy 1	2022-03-22	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: VCV000164350, PMID:12707239). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:25132132). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.942>=0.6, 3CNET: 0.993>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000770495	SCV004100301	pathogenic	Cardiomyopathy	2023-09-05	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.2011C>T (p.Arg671Cys) results in a non-conservative amino acid change in 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 252082 control chromosomes. c.2011C>T has been reported in the literature in multiple individuals affected with Cardiomyopathy (e.g. Mohiddin_2003, Richard_2003, Wang_2014, Zhao_2021, Chida_2017, Walsh_2017). Additionally it was observed de novo patient (Zhao_2021) and in a family with Cardiomyopathy (Chida_2017). These data indicate that the variant is very likely to be associated with disease. 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: 27885498, 12820698, 12707239, 27532257, 25132132, 32381727). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=1) and pathogenic/likely pathogenic (n=7). Based on the evidence outlined above, the variant was classified as pathogenic.