Submissions for variant NM_002471.4(MYH6):c.5653G>A (p.Glu1885Lys)

gnomAD frequency: 0.00001  dbSNP: rs760353963

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000647068	SCV000768855	uncertain significance	Hypertrophic cardiomyopathy 14	2023-09-17	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 537966). This missense change has been observed in individual(s) with a MYH6-related disease and Wolff–Parkinson–White syndrome (PMID: 26284702, 27760138). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs760353963, gnomAD 0.006%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1885 of the MYH6 protein (p.Glu1885Lys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280662	SCV001467952	uncertain significance	not specified	2020-12-14	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.5653G>A (p.Glu1885Lys) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251416 control chromosomes (gnomAD). c.5653G>A has been reported to segregate with Wolff Parkinson White syndrome in a family (Bowles_2015). The variant was also reported in an individual who died of hypoplastic left heart syndrome and her unaffected mother. The patient was however, compound heterozygous for the variant of interest and another MYH6 variant (Preuss_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002343326	SCV002651848	uncertain significance	Cardiovascular phenotype	2023-11-21	criteria provided, single submitter	clinical testing	The p.E1885K variant (also known as c.5653G>A), located in coding exon 35 of the MYH6 gene, results from a G to A substitution at nucleotide position 5653. The glutamic acid at codon 1885 is replaced by lysine, an amino acid with similar properties. This alteration has been reported to segregate in a family with Wolff-Parkinson-White syndrome (Bowles NE et al. Am J Med Genet A, 2015 Dec;167A:2975-84). This alteration was also reported as a compound heterozygote in an infant with hypoplastic left heart syndrome (Preuss C et al. PLoS Genet, 2016 Oct;12:e1006335). 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.
GeneDx	RCV001530021	SCV004023924	uncertain significance	not provided	2024-04-22	criteria provided, single submitter	clinical testing	Reported in a patient with congenital heart disease who harbored an additional MYH6 variant in trans (PMID: 27760138) and in multiple affected individuals from a single family with Wolff-Parkinson-White syndrome (PMID: 26284702); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35779862, 32233023, 26284702, 27760138)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530021	SCV001744512	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001530021	SCV001926327	uncertain significance	not provided		no assertion criteria provided	clinical testing