Submissions for variant NM_000257.4(MYH7):c.3134G>T (p.Arg1045Leu)

dbSNP: rs397516178

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000629019	SCV001976477	likely pathogenic	Hypertrophic cardiomyopathy	2021-08-25	reviewed by expert panel	curation	The c.3134G>T (p.Arg1045Leu) variant in MYH7 has been reported in at least 15 individuals with HCM (PS4_Moderate; Cann 2017 PMID:27000522; Sheikh 2018 PMID:29764897, Walsh 2017 PMID:27532257; GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.), 4 of whom also had additional variants in other HCM-associated genes (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). Because of the additional variants observed in multiple cases, PS4 was downgraded to Moderate. This variant also segregated with HCM in 6 affected relatives from 3 families (PP1_Moderate; Cann 2017 PMID:27000522; GeneDx pers. comm., LMM pers. comm., OMGL pers. comm.). This variant has also been identified in 0.001% (FAF 95% CI, 4/113744) of European chromosomes in gnomAD v2.1.1 (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 (Kelly 2018 PMID:29300372): PS4_Moderate; PP1_Moderate; PM2; PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000629019	SCV000059492	likely pathogenic	Hypertrophic cardiomyopathy	2019-12-18	criteria provided, single submitter	clinical testing	The p.Arg1045Leu variant in MYH7 has been identified in at least 11 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 4 affected relatives from 3 families (Cann 2017, Walsh 2017, Invitae pers. comm., GeneDx pers. comm., LMM data). It has also been identified in 1 individual with HCM who carried an additional pathogenic variant in MYH7 (LMM data). This variant has also reported by other clinical laboratories in ClinVar (Variation ID#42948) and has been identified in 0.004% (4/113744) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg1045Cys) has been identified in individuals with HCM and is classified as likely pathogenic by this laboratory. 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: PM2, PP1, PP3, PS4_Moderate, PM5_Supporting.
GeneDx	RCV001703459	SCV000208523	likely pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing	Reported in several individuals with HCM (Alfares et al., 2015; Cann et al., 2016; Walsh et al., 2015), and reported as p.(R1045L) (c.3134G>T) in another individual with HCM (de Marvao et al., 2021); 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: 25611685, 27532257, 31447099, 27247418, 34542152, 34636345, 34503678, 27000522)
Invitae	RCV000629019	SCV000749929	pathogenic	Hypertrophic cardiomyopathy	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1045 of the MYH7 protein (p.Arg1045Leu). This variant is present in population databases (rs397516178, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42948). 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.Arg1045 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18533079, 20215591, 24793961, 26914223, 27247418, 27532257). 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.
Color Diagnostics, LLC DBA Color Health	RCV001188088	SCV001355056	likely pathogenic	Cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 1045 in the neck and hinge domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 27000522, 27532257, 29764897, 33495596, 33495597; ClinVar SCV001976477.1). Several of these individuals also carried variants in other genes associated with hypertrophic cardiomyopathy (ClinVar SCV001976477.1). It has been shown that this variant segregates with disease in 6 affected individuals across 3 families (ClinVar SCV001976477.1). This variant has also been reported in one individual affected with dilated cardiomyopathy (PMID: 35732239). This variant has been identified in 4/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg1045Cys, is considered to be disease-causing (ClinVar variation ID: 177753), suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258092	SCV001434936	likely pathogenic	Hypertrophic cardiomyopathy 1	2018-10-12	criteria provided, single submitter	clinical testing	This c.3134G>T (p.Arg1045Leu) variant in the MYH7 gene has been reported in at least three unrelated patients with hypertrophic cardiomyopathy (PMID 25611685, 26914223, 27247418) and is extremely rare in general population databases. A second variant in the same codon, p. Arg1045His was classified likely pathogenic by our laboratory. A third variant at this codon, p.Arg1045Cys was classified as likely pathogenic by expert panel in the Clinvar database, suggesting this arginine residue is critical for MYH7 protein function. Multiple lines of prediction algorithms support the deleterious effect of the c.3134G>T (p.Arg1045Leu) variant. Therefore, this c.3134G>T (p.Arg1045Leu) variant in the MYH7 gene is classified as likely pathogenic.
Ambry Genetics	RCV002321503	SCV002607568	likely pathogenic	Cardiovascular phenotype	2022-12-12	criteria provided, single submitter	clinical testing	The p.R1045L variant (also known as c.3134G>T), located in coding exon 23 of the MYH7 gene, results from a G to T substitution at nucleotide position 3134. The arginine at codon 1045 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in numerous hypertrophic cardiomyopathy cohorts and has been reported to segregate with disease in several families (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med., 2017 02;19:192-203; Sheikh N et al. Circulation, 2018 Sep;138:1184-1194; GeneDx pers comm; Invitae pers comm; LMM pers comm; OMGL pers comm). An alternate amino acid substitution at this position, p.R1045C, has also been reported in HCM cases (Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496541	SCV002809753	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	2021-09-23	criteria provided, single submitter	clinical testing