Submissions for variant NM_002471.4(MYH6):c.3619G>A (p.Glu1207Lys)

gnomAD frequency: 0.00006  dbSNP: rs397516762

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037481	SCV000061139	uncertain significance	not specified	2016-04-27	criteria provided, single submitter	clinical testing	The p.Glu1207Lys variant in MYH6 has been reported in the literature in 1 indivi dual with hypoplastic left heart (Theis 2015) and has been observed by our labor atory in 1 individual with HCM. This variant has been identified in 11/63888 Eur opean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs397516762). Computational prediction tools and conservation analysis suggest that the p.Glu1207Lys variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu1207Lys variant is uncertain.
Ambry Genetics	RCV000618370	SCV000735297	uncertain significance	Cardiovascular phenotype	2023-03-14	criteria provided, single submitter	clinical testing	The p.E1207K variant (also known as c.3619G>A), located in coding exon 24 of the MYH6 gene, results from a G to A substitution at nucleotide position 3619. The glutamic acid at codon 1207 is replaced by lysine, an amino acid with some similar properties. This alteration was reported in a proband with hypoplastic left heart syndrome who also carried a second missense alteration in MYH6; the p.E1207K alteration was also seen in the proband's unaffected father (Theis JL. Circ Cardiovasc Genet. 2015 Aug;8(4):564-71). This variant also co-occurred with a variant in the LMNA gene in an individual with dilated cardiomyopathy (van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309). This variant was also reported in a pediatric cardiomyopathy cohort (Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822261	SCV000963054	uncertain significance	Hypertrophic cardiomyopathy 14	2022-11-29	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs397516762, gnomAD 0.01%). 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 MYH6 protein function. ClinVar contains an entry for this variant (Variation ID: 44488). This missense change has been observed in individual(s) with hypoplastic left heart (PMID: 26085007). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1207 of the MYH6 protein (p.Glu1207Lys).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001753447	SCV001471709	uncertain significance	not provided	2020-01-31	criteria provided, single submitter	clinical testing	The MYH6 c.3619G>A; p.Glu1207Lys variant (rs397516762) is reported in the literature in an individual affected with hypoplastic left heart (Theis 2015). This variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (19/127454 alleles) in the Genome Aggregation Database. The glutamate at codon 1207 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Glu1207Lys variant is uncertain at this time. References: Theis JL et al. Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction. Circ Cardiovasc Genet. 2015 Aug;8(4):564-71.
GeneDx	RCV001753447	SCV001987694	uncertain significance	not provided	2023-12-12	criteria provided, single submitter	clinical testing	Has been reported in individuals with hypoplastic left heart syndrome and cardiomyopathy (PMID: 26085007, 30847666, 35026164); 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: 33432820, 35026164, 35621855, 33949037, 30847666, 26085007)
AiLife Diagnostics, AiLife Diagnostics	RCV001753447	SCV002501580	uncertain significance	not provided	2021-06-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037481	SCV002555922	uncertain significance	not specified	2022-06-16	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.3619G>A (p.Glu1207Lys) 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 8.4e-05 in 249396 control chromosomes, predominantly at a frequency of 0.00016 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3619G>A has been reported in the literature in a proband affected with hypoplastic left heart syndrome, having been inherited from her unaffected father (Theis_2015). In addition, a ClinVar submitter reports detection of the variant in one individual with HCM (SCV000061139.5). 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. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Fulgent Genetics, Fulgent Genetics	RCV002490508	SCV002797659	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-08-09	criteria provided, single submitter	clinical testing