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

gnomAD frequency: 0.00001  dbSNP: rs760187215

Total submissions: 9

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.
Invitae	RCV001207953	SCV001379321	uncertain significance	Hypertrophic cardiomyopathy	2023-01-14	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 619082). 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. 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. This missense change has been observed in individual(s) with MYH7-related conditions (PMID: 27532257, 34935411). This variant is present in population databases (rs760187215, gnomAD 0.003%). 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).
Ambry Genetics	RCV002343609	SCV002649346	uncertain significance	Cardiovascular phenotype	2019-03-05	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 alteration has been reported in a dilated cardiomyopathy clinical genetic testing cohort; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203). 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