rs730880961
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_000258.3(MYL3):c.280C>T(p.Arg94Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94H) has been classified as Pathogenic.
Frequency
Consequence
NM_000258.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYL3 | NM_000258.3 | c.280C>T | p.Arg94Cys | missense_variant | 3/7 | ENST00000292327.6 | NP_000249.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYL3 | ENST00000292327.6 | c.280C>T | p.Arg94Cys | missense_variant | 3/7 | 1 | NM_000258.3 | ENSP00000292327.4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251306Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135848
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461758Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15AN XY: 727190
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 24, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 94 of the MYL3 protein (p.Arg94Cys). This variant is present in population databases (rs730880961, gnomAD 0.01%). This missense change has been observed in individuals with cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 32009526; Invitae). ClinVar contains an entry for this variant (Variation ID: 181448). 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. This variant disrupts the p.Arg94 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18409188, 23283745, 26443374, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 17, 2024 | This missense variant replaces arginine with cysteine at codon 94 of the MYL3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with cardiomyopathy (PMID: 32009526). This variant has been identified in 6/251306 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg94His, is considered to be disease-causing (ClinVar variation ID: 31777), suggesting that arginine at this position is important for MYL3 protein function. 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. - |
Uncertain significance, no assertion criteria provided | research | Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics | - | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 02, 2023 | This missense variant replaces arginine with cysteine at codon 94 of the MYL3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 cardiomyopathy (PMID: 32009526). This variant has also been identified in 6/251306 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2023 | Reported in association with cardiomyopathy in the published literature (Pottinger et al., 2020); 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: 32009526) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2022 | The p.R94C variant (also known as c.280C>T), located in coding exon 3 of the MYL3 gene, results from a C to T substitution at nucleotide position 280. The arginine at codon 94 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in an individual with cardiomyopathy from an electronic medical records cohort; however, clinical details were limited, and an MYBPC3 variant was also detected (Pottinger TD et al. J Am Heart Assoc, 2020 02;9:e013808). Another alteration at the same codon, p.R94H (c.281G>A), has been described in individuals and families with hypertrophic cardiomyopathy (Fokstuen S et al. Hum Mutat, 2008 Jun;29:879-85; Nomura A et al. J Cardiol, 2016 Feb;67:133-9; Walsh R et al. Genet Med, 2017 02;19:192-203). This amino acid position is not well 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at