ClinVar Genomic variation as it relates to human health

The p.Glu177Gly variant in MYL3 has been reported in at least 5 individuals with HCM (Jay 2013 PMID: 23594557, Lopes 2015 PMID: 25351510; Burstein 2021 PMID: 32746448, Ambry and GeneDx personal communication; ClinVar Variation ID 36648), but was also identified in 0.3% (1/316) of Middle Eastern and 0.02% (1/3470) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database, v. 3 (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922391). This variant has also been reported in ClinVar (Variation ID 36648). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu177Gly variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PP3, BS1.

The c.530A>G (p.E177G) alteration is located in exon 5 (coding exon 5) of the MYL3 gene. This alteration results from a A to G substitution at nucleotide position 530, causing the glutamic acid (E) at amino acid position 177 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Reported in association with hypertrophic cardiomyopathy (Bick et al., 2012; Jay et al., 2013); 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: 25637381, 22958901, 23594557, 25351510, 30706179, 31618753)

Variant summary: MYL3 c.530A>G (p.Glu177Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 121730 control chromosomes. The observed variant frequency is approximately 1.97 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYL3 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05). However, only 6 occurrences were found in controls, which is too low to make a conclusion. c.530A>G has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 177 of the MYL3 protein (p.Glu177Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 23594557, 31618753, 32746448; Invitae). ClinVar contains an entry for this variant (Variation ID: 36648). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

This missense variant replaces glutamic acid with glycine at codon 177 of the MYL3 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). This variant does not affect the rate of myosin interaction with actin but increasing calcium sensitivity (PMID: 36509720). This variant has been reported in an infant affected with hypertrophic cardiomyopathy as well as his asymptomatic father (PMID: 23594557). This variant has also been reported in nine additional individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 30847666, 31618753, 32746448, 37431535), and in one individual with abnormality of the cardiovascular system (PMID: 26633542). This variant has also been observed in several unaffected individuals (PMID: 22958901, 37431535). This variant has been identified in 16/282568 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.

This missense variant replaces glutamic acid with glycine at codon 177 of the MYL3 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 infant affected with hypertrophic cardiomyopathy as well as his asymptomatic father (PMID: 23594557). This variant has also been reported in another four individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 30847666; ClinVar SCV000740165.3 and SCV000208890.11), in one individual with abnormality of the cardiovascular system (PMID: 26633542), in one individual affected with cardiomyopathy and progressive muscle weakness (PMID: 31618753), and in an individual with left ventricular wall thickness, left ventricular diastolic diameter and left atrial diameter within the normal range (PMID: 22958901). This variant has been identified in 16/282568 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.

The missense variant c.530A>G(p.Glu177Gly) in MYL3 gene has been reported in an infant affected with hypertrophic cardiomyopathy (Jay et. al., 2013). His father who also carried the variant was asymptomatic. This variant has also been reported in an individual with left ventricular wall thickness, left ventricular diastolic diameter and left atrial diameter within the normal range (Bick et. al., 2012). The p.Glu177Gly variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.005% in gnomAD exomes database. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid change p.Glu177Gly in MYL3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 177 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu177Gly (c.530A>G). We consider it a variant of unknown significant, primarily based on a lack of strength in the available case data and a lack of controls matching our patient’s ancestry (and ancestry of one of the cases). One case was reported by Jay et al (2013): an Iraqi-American baby HCM with only this variant found on an 18 gene panel at GeneDx. The proband's father also carried the variant and reportedly had a normal echo (though not reviwed by the authors). MYL3 is one of the rarer HCM genes and it has not been studied as extensively as the more common ones. In a meta-analysis that included sequencing of MYL3 in 883 patients with HCM from several different centers, only one individual had an MYL3 variant thought to be disease causing (van Driest et al 2005). MYL3 was first linked to HCM in 1996 when a group from the NIH identified p.Met149Val in 1 of 383 unrelated HCM patients in their cohort (Poetter et al 1996). The variant segregated with disease in 12 affected family members with a LOD score of 6.2. Of note, p.Met149Val was not observed in the ~5400 individuals in the current version of the NHLBI ESP data set (June 25th, 2012). This is a non-conservative amino acid change with a polar Glutamine replaced with a non-polar Glycine. Conservation analysis indicates that Glutamine is highly conserved at this position in the MYL3 gene. In silico analysis predicts the amino acid change to be probably damaging to the protein (Ramensky V et al 2002). In addition, GeneDx noted that they found a nearby variant (p.Met173Val) in HGMD that was reported in association with HCM. In total, the variant has been seen in 2/8666 publicly available general population samples and private laboratory controls. Note that none of these samples match the patient’s ancestry. GeneDx reports that p.Glu177Gly was not identified in 200 presumably healthy control individuals of either Caucasian or African American ancestry. The variant has not been reported in dbSNP or 1000Genomes (as of June 2012). The variant is reported in 1/4,300 Caucasian individuals and 0/2,203 African American individuals in the NHLBI ESP dataset (as of June 25th, 2012). The phenotype of that particular individual is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. The Seidman group observed the variant in 1 of 1963 unrelated individuals from the Jackson Heart Study (Bick et al 2012). That individual had a left ventricular wall thickness of 1.1 cm and two physiological risk factors (could include hyperlipidemia, hypertension, obesity, or diabetes).

The MYL3 c.530A>G variant is predicted to result in the amino acid substitution p.Glu177Gly. This variant has been reported in the heterozygous and homozygous states in individuals with hypertrophic cardiomyopathy (see, for example, Jay et al. 2013. PubMed ID: 23594557; Allouba et al. 2023. PubMed ID: 37431535; Table S8, McGurk et al. 2023. PubMed ID: 37652022). It has also been identified in unaffected individuals (Allouba et al. 2023. PubMed ID: 37431535; Table S8, McGurk et al. 2023. PubMed ID: 37652022). An in vitro experimental study indicated this variant did not affect the sliding velocity of F-actin compared to wild type, but calcium sensitivity was increased (Yampolskaya et al. 2022. PubMed ID: 36509720). This variant is reported in 0.039% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.