ClinVar Miner

Submissions for variant NM_000432.3(MYL2):c.170G>A (p.Gly57Glu) (rs199474809)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620413 SCV000736704 uncertain significance Cardiovascular phenotype 2016-11-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000119378 SCV000208857 uncertain significance not provided 2017-02-13 criteria provided, single submitter clinical testing The G57E variant has been reported in one individual with restrictive cardiomyopathy (Caleshu C et al., 2011). This patient was a 22-year-old female who was homozygous for a E143L variant in the MYL3 gene, and heterozygous for the G57E variant in the MYL2 gene. Her unaffected mother was heterozygous for both changes. G57E results in a non-conservative amino acid substitution of a non-polar Glycine residue with a negatively charged Glutamic acid residue at a position that is conserved through evolution. Missense variants in nearby residues (N47K, R58Q, E65K) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the G57E variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000819932 SCV000960619 uncertain significance Familial hypertrophic cardiomyopathy 10 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 57 of the MYL2 protein (p.Gly57Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with restrictive cardiomyopathy and hypertrophic cardiomyopathy (PMID: 21823217, 25611685, 27532257). ClinVar contains an entry for this variant (Variation ID: 43458). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036384 SCV000060039 uncertain significance not specified 2018-07-16 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly57Glu variant in MYL2 has been reported in one individual with clinical features of RC M, who also carried the homozygous p.Glu134Lys missense variant in MYL3 and whos e unaffected mother was heterozygous for both variants (Caleshu 2011). The p.Gly 57Glu variant in MYL2 has also been identified in 2 infants with HCM, both of wh om also carried another variant of uncertain significance (p.Glu134Ala) in MYL2 (LMM data). In one of these probands, the p.Gly57Glu variant was found to be pat ernally inherited and the proband's father had LVH. The p.Gly57Glu variant has b een identified in 1/33580 of Latino chromosomes by the Genome Aggregation Databa se (gnomAD, Computational prediction tools an d conservation analysis suggest that the p.Gly57Glu variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In addition, this variant is located in the first base of the exon, which is pa rt of the 3? splice region; however, computational splicing prediction tools do not suggest an impact to splicing. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Gly57Glu variant is uncer tain. ACMG/AMP Criteria applied: PM2, PP3, PS4_Supporting.
Leiden Muscular Dystrophy (MYL2) RCV000119378 SCV000154285 not provided not provided no assertion provided not provided

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