Submissions for variant NM_000432.4(MYL2):c.170G>A (p.Gly57Glu)

gnomAD frequency: 0.00001  dbSNP: rs199474809

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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, http://gnomad.broadinstitute.org). 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.
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.
Ambry Genetics	RCV000620413	SCV000736704	uncertain significance	Cardiovascular phenotype	2024-07-25	criteria provided, single submitter	clinical testing	The p.G57E variant (also known as c.170G>A), located in coding exon 4 of the MYL2 gene, results from a G to A substitution at nucleotide position 170. This variant impacts the first base pair of coding exon 4. The glycine at codon 57 is replaced by glutamic acid, an amino acid with some similar properties. This alteration has been reported in a subject with restrictive cardiomyopathy who was also homozygous for a missense alteration in MYL3. The unaffected mother was heterozygous for both variants (Caleshu C et al. Am. J. Med. Genet. A, 2011 Sep;155A:2229-35). This variant has also been detected in a hypertrophic cardiomyopathy genetic testing cohort (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819932	SCV000960619	uncertain significance	Hypertrophic cardiomyopathy 10	2024-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 57 of the MYL2 protein (p.Gly57Glu). This variant is present in population databases (rs199474809, gnomAD 0.003%). This missense change has been observed in individual(s) with restrictive cardiomyopathy and hypertrophic cardiomyopathy (PMID: 21823217, 25611685, 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 43458). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Color Diagnostics, LLC DBA Color Health	RCV001187128	SCV001353813	uncertain significance	Cardiomyopathy	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 57 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with restrictive cardiomyopathy (PMID: 21823217). This patient was heterozygous for this variant and homozygous for a p.Glu143Leu variant in the MYL3 gene. The patient's unaffected mother was double heterozygous for both variants. This variant has also been reported in two individuals affected with hypertrophic cardiomyopathy, both of whom also carried the MYL3 p.Glu134Ala variant (PMID: 25611685, 27532257). This variant has been identified in 1/251442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000119378	SCV003817785	uncertain significance	not provided	2020-03-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996220	SCV004845857	uncertain significance	Hypertrophic cardiomyopathy	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 57 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with restrictive cardiomyopathy (PMID: 21823217). This patient was heterozygous for this variant and homozygous for a p.Glu143Leu variant in the MYL3 gene. The patient's unaffected mother was double heterozygous for both variants. This variant has also been reported in two individuals affected with hypertrophic cardiomyopathy, both of whom also carried the MYL3 p.Glu134Ala variant (PMID: 25611685, 27532257). This variant has been identified in 1/251442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Leiden Muscular Dystrophy (MYL2)	RCV000119378	SCV000154285	not provided	not provided		no assertion provided	not provided