Submissions for variant NM_000257.4(MYH7):c.541G>A (p.Gly181Arg)

gnomAD frequency: 0.00001  dbSNP: rs760187215

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000757956	SCV000882824	likely pathogenic	Primary dilated cardiomyopathy; Left ventricular noncompaction cardiomyopathy	2018-12-06	criteria provided, single submitter	research	The c.541G>A (p.G181R) variant was previously reported in HGMD database (CM1616486) as a DM(disease causing mutation) and in Atlas of Cardiac Genetic Variations. This is a rare variant with low frequency in population databases. Computational evidence supports a deleterious effect. Also c.541G>A (p.G181R) is located in a domain without benign variation (Walsh et al., 2017). We consider this evidence enough to classify c.541G>A (p.G181R) as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001207953	SCV001379321	uncertain significance	Hypertrophic cardiomyopathy	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 181 of the MYH7 protein (p.Gly181Arg). This variant is present in population databases (rs760187215, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant MYH7-related conditions (PMID: 27532257, 34935411, 37652022). ClinVar contains an entry for this variant (Variation ID: 619082). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002343609	SCV002649346	uncertain significance	Cardiovascular phenotype	2024-07-18	criteria provided, single submitter	clinical testing	The p.G181R variant (also known as c.541G>A), located in coding exon 5 of the MYH7 gene, results from a G to A substitution at nucleotide position 541. The glycine at codon 181 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in individuals reported to have dilated and/or noncompaction cardiomyopathy; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203; van Waning JI et al. J Am Coll Cardiol. 2018 Feb;71(7):711-722; Khan RS et al. J Am Heart Assoc. 2022 Jan;11(1):e022854; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150341	SCV003838769	uncertain significance	Cardiomyopathy	2021-06-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333106	SCV004041160	uncertain significance	Myopathy, myosin storage, autosomal recessive	2023-03-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333107	SCV004041236	uncertain significance	Myosin storage myopathy	2023-03-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333104	SCV004041260	uncertain significance	MYH7-related skeletal myopathy	2023-03-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333105	SCV004041456	uncertain significance	Hypertrophic cardiomyopathy 1	2023-03-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333103	SCV004041538	uncertain significance	Dilated cardiomyopathy 1S	2023-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240534	SCV005885001	uncertain significance	not specified	2024-12-20	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.541G>A (p.Gly181Arg) 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 allele was found at a frequency of 8e-06 in 251478 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.541G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Walsh_2017, Khan_2021, McGurk_2023). These reports 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: 27318203, 28606303, 34935411, 37652022, 27532257, 29447731). ClinVar contains an entry for this variant (Variation ID: 619082). Based on the evidence outlined above, the variant was classified as uncertain significance.