Submissions for variant NM_000257.4(MYH7):c.611G>A (p.Arg204His)

gnomAD frequency: 0.00003  dbSNP: rs397516260

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000543200	SCV000059642	likely pathogenic	Hypertrophic cardiomyopathy	2021-04-29	criteria provided, single submitter	clinical testing	The p.Arg204His variant in MYH7 has been observed in >20 probands with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 1 affected family member (Richard 2003 PMID: 12707239, Meyer 2013 PMID: 23816408, Su 2014 PMID: 24865491, Berge 2014 PMID: 24111713, Ntusi 2016 PMID: 27841901, Furqan 2017 PMID: 28986452, Walsh 2017 PMID: 27532257, LMM data). At least 5 of the affected individuals carried additional disease-causing variants cardiomyopathy associated genes that may have also contributed to their phenotypes (Furqan 2017, LMM data). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 43095). It has also been identified in 0.0023% (3/129190) of European chromosomes in gnomAD (https://gnomad.broadinstitute.org). 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 2017 PMID: 27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. 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, PM1, PM2_Supporting.
GeneDx	RCV000223767	SCV000208684	likely pathogenic	not provided	2024-06-13	criteria provided, single submitter	clinical testing	Reported in a patient with early-onset atrial fibrillation in published literature (PMID: 34495297); Identified in a patient with clinically diagnosed limb-girdle muscular dystrophy (LGMD) who harbored an additional pathogenic variant in the CAPN3 gene (PMID: 29970176); 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: 20439259, 24865491, 12707239, 27532257, 27247418, 24111713, 27841901, 20975235, 23074333, 23816408, 28986452, 28790153, 32894683, 35982159, 31843643, 34542152, 35653365, 37377035, 36243179, 34495297, 29970176, 29300372, 37652022)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543200	SCV000623754	pathogenic	Hypertrophic cardiomyopathy	2024-01-15	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 204 of the MYH7 protein (p.Arg204His). This variant is present in population databases (rs397516260, gnomAD 0.005%). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (PMID: 12707239, 23816408, 24111713, 24865491, 27247418, 27532257, 27841901). ClinVar contains an entry for this variant (Variation ID: 43095). 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 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170746	SCV001333351	likely pathogenic	Cardiomyopathy	2023-03-29	criteria provided, single submitter	clinical testing	The c.611G>A variant in MYH7 causes an amino acid substitution, which replaces arginine with histidine at position 204. It was identified in 5/282888 (0.0003%) of alleles tested from control populations in the Genome Aggregation Database (gnomAD), including in 0.005% of alleles tested from the East Asian population, and is neither sufficiently rare to provide evidence in favor of pathogenicity nor sufficiently common to provide evidence against pathogenicity. It has been previously reported in at least 15 apparently unrelated individuals with hypertrophic cardiomyopathy (PMID 12707239, 20975235, 23074333, 23816408, 24111713, 24865491, 27532257, 27841901, 28986452, and others). This variant was reported to segregate with disease in one family (PMID 28986452). This variant is located within the head region (codons 181-937) of the Myosin-7 protein (NM_000257.2; NP_000248.2), where MYH7 pathogenic variants are significantly clustered (PMID 29300372). Alternate amino acid substitutions have been previously established as pathogenic at the 204 residue, c.611G>T, p.Arg204Leu, in patients with hypertrophic cardiomyopathy (PMID 27532257, ClinVar database). The Arg204 residue is highly conserved across evolutionarily distant species. In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function. This variant is listed in ClinVar (VCV000043095). Based on the above information, we categorize this variant as likely pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256696	SCV001433097	likely pathogenic	Hypertrophic cardiomyopathy 1	2020-01-06	criteria provided, single submitter	clinical testing
3billion	RCV001256696	SCV002059154	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: VCV000043095, PMID:12707239, PS1_S). A different missense change at the same codon has been reported to be associated with MYH7 related disorder (PMID:27247418, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.655, 3CNET: 0.958, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000018, PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002354191	SCV002661107	likely pathogenic	Cardiovascular phenotype	2023-08-21	criteria provided, single submitter	clinical testing	The p.R204H variant (also known as c.611G>A), located in coding exon 5 of the MYH7 gene, results from a G to A substitution at nucleotide position 611. The arginine at codon 204 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 a number of hypertrophic cardiomyopathy cohorts (Richard P et al. Circulation. 2003;107:2227-32; Funada A et al. Circ. J. 2010;74:2674-80; Meyer T et al. Gene. 2013;527:416-20; Berge KE et al. Clin. Genet. 2014;86:355-60; Su M et al. Int J Mol Sci. 2014;15:9302-13; Ntusi NA et al. Cardiovasc J Afr. 2016;27:152-158; Burns C et al. Circ Cardiovasc Genet. 2017;10:e001666; Walsh R et al. Genet. Med. 2017;19:192-203). This amino acid position is 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.
Baylor Genetics	RCV003147324	SCV003835318	pathogenic	Dilated cardiomyopathy 1S	2022-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001256696	SCV003835385	pathogenic	Hypertrophic cardiomyopathy 1	2022-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147327	SCV003835386	pathogenic	MYH7-related skeletal myopathy	2022-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147328	SCV003835387	pathogenic	Myopathy, myosin storage, autosomal recessive	2022-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003320092	SCV003835448	pathogenic	Myosin storage myopathy	2022-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003320092	SCV003835540	pathogenic	Myosin storage myopathy	2022-09-05	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223767	SCV000280373	likely pathogenic	not provided	2014-09-24	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. Review of data on p.Arg204His in MYH7 Summary: -Seen in at least 20 presumably unrelated cases of HCM (5 published, 15 unpublished). -3 of 20 cases who had sequencing of at least MYH7 and MYBPC3 had another sarcomere variant: -----Late 50s female with HCM and fhx of CHF and sudden death, carried another MYH7 variant (classified as likely pathogenic by LMM) -----Late 30s female with HCM and fhx of sudden death, carried an MYBPC3 variant (frameshift variant, LMM classified as pathogenic) -----Woman diagnosed at 72yo with LVWT 15 mm and an MYL2 variant (GeneDx classifies as variant of uncertain significance) -3 of 20 cases had an additional variant in a non-sarcomere gene: -----A 53yo male with LVWT 20 mm and a daughter with HCM carried a variant of uncertain significance in MTTG -----A patient carried a variant in MuRF2 that the authors hypothesize is a modifier -----Late 40s female with LVH and NSVT and fhx of “possible HCM/enlarged heart and sudden death, and carried a variant in PKP2 (-1 splice variant, LMM classified as likely pathogenic) -There is weak segregation data. In at least one family an additional affected relative carried this variant. -The variant was not observed in a total of ~61,161 individuals from published controls and publicly available datasets that were not selected for HCM. Published cases: Richard et al. (2003) reported this variant in one out of 197 patients diagnosed with HCM that were cared for in Paris, France, who underwent analysis of the MYH7, MYBPC3, MYL2, MYL3, TNNI3, and TNNT2 genes. This case is most likely redundant with a later report by the same group (Gandjbakhch et al. 2010). Meyer et al. (2013) reported this variant in one out of 8 patients diagnosed with HCM that were cared for in Marburg, Germany, who underwent analysis of MYH7 and MYBPC3. No other phenotypic information was reported in the paper. Berge et al. (2014) reported this variant in one out of 696 patients diagnosed with HCM that were cared for in Norway, who underwent analysis of the MYH7, MYBPC3, TNNI3, TNNT2, MYL2, and MYL3 genes. No other phenotypic information was reported in the paper. Su et al. (2014) reported this variant in 2 patients diagnosed with HCM that were cared for in Beijing, China, who underwent analysis of MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1, MuRF1, MuRF2, and MuRF3 genes. One of the two patients carries a second variant in MuRF2 gene (c.1516A>T; p.T506S). Authors propose that rare variants in MuRF2 genes increase the risk of development of HCM and lead to more severe disease phenotypes, and thus may act as modifiers of the disease. This variant substitutes a polar, positively charged amino acid (Arg) with a polar, positively charged amino acid (His). In silico analysis with PolyPhen-2 predicts the variant to be “possibly damaging” and SIFT predicts the variant to be “deleterious.” The Arginine at codon 204 is moderately conserved across species, as are neighboring amino acids. It is highly conserved among mammals. Other variants have been reported in association with disease at this codon (c.610C>T (p.Arg204Cys) with classification as pathogenic by GeneDx in ClinVar, no other submitters; c.611G>T (p.Arg204Leu) with conflicting classifications in ClinVar) and nearby codons (p.Ala199Val; p.Ile201Thr (Villard, 2005); p.Lys207Gln (Mohiddin, 2003)). The variant was not observed in ~61,113 individuals from published controls and publicly available datasets that approximate the general population. This includes ~60,706 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of April 22nd, 2015). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population; others were enriched for common cardiovascular disease. They were not selected for HCM and in some cases Mendelian heart disease was excluded. This variant is currently listed in dbSNP: rs397516260. The variant was not observed in the following published control samples: Richard (2003) did not report this variant in 100 control individuals, Su (2014) did not report this variant in 307 control individuals.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000223767	SCV001932172	uncertain significance	not provided		flagged submission	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000223767	SCV001968424	uncertain significance	not provided		flagged submission	clinical testing