Submissions for variant NM_002471.4(MYH6):c.5491G>A (p.Glu1831Lys)

gnomAD frequency: 0.00006  dbSNP: rs367834703

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177872	SCV000229824	uncertain significance	not provided	2015-06-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004020118	SCV000742296	uncertain significance	Cardiovascular phenotype	2022-11-23	criteria provided, single submitter	clinical testing	The p.E1831K variant (also known as c.5491G>A), located in coding exon 34 of the MYH6 gene, results from a G to A substitution at nucleotide position 5491. The glutamic acid at codon 1831 is replaced by lysine, an amino acid with similar properties. This variant was detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This alteration was also detected in a hypertrophic cardiomyopathy (HCM) cohort (Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445). 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.
Invitae	RCV001229276	SCV001401718	uncertain significance	Hypertrophic cardiomyopathy 14	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1831 of the MYH6 protein (p.Glu1831Lys). This variant is present in population databases (rs367834703, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 196975). 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 MYH6 protein function with a positive predictive value of 80%. 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.
GeneDx	RCV000177872	SCV001770624	uncertain significance	not provided	2020-01-28	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 196975; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Fulgent Genetics, Fulgent Genetics	RCV002478588	SCV002788846	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-09-01	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318363	SCV004022008	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PP3
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000177872	SCV005199364	uncertain significance	not provided	2023-08-17	criteria provided, single submitter	clinical testing