12-110919145-A-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000432.4(MYL2):āc.52T>Cā(p.Phe18Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F18S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000432.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYL2 | NM_000432.4 | c.52T>C | p.Phe18Leu | missense_variant | 2/7 | ENST00000228841.15 | |
MYL2 | NM_001406745.1 | c.52T>C | p.Phe18Leu | missense_variant | 2/6 | ||
MYL2 | NM_001406916.1 | c.-6T>C | 5_prime_UTR_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYL2 | ENST00000228841.15 | c.52T>C | p.Phe18Leu | missense_variant | 2/7 | 1 | NM_000432.4 | P1 | |
MYL2 | ENST00000548438.1 | c.52T>C | p.Phe18Leu | missense_variant | 2/6 | 3 | |||
MYL2 | ENST00000546404.1 | c.52T>C | p.Phe18Leu | missense_variant | 2/2 | 2 | |||
MYL2 | ENST00000663220.1 | c.-6T>C | 5_prime_UTR_variant | 2/7 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461652Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727098
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 10 Pathogenic:2Other:1
not provided, no classification provided | curation | Leiden Muscular Dystrophy (MYL2) | Mar 26, 2012 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MYL2 function (PMID: 11102452, 12668451, 14594949, 25324513). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 14068). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9535554). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 18 of the MYL2 protein (p.Phe18Leu). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1998 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2022 | Published functional studies suggest a damaging effect through decreased calcium sensitivity and altered phosphorylation (Szczesna et al., 2001; Roopnarine 2003; Szczesna-Cordary et al., 2004) ); Not observed at significant frequency in large population cohorts (gnomAD); 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: 14594949, 25324513, 9535554, 12668451, 11102452) - |
Hypertrophic cardiomyopathy 10;C5561937:Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 03, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2015 | The p.F18L variant (also known as c.52T>C), located in coding exon 2 of the MYL2 gene, results from a T to C substitution at nucleotide position 52. The phenylalanine at codon 18 is replaced by leucine, an amino acid with highly similar properties. This variant has been described in patients with hypertrophic cardiomyopathy (HCM) (Flavigny J et al. J Mol Med. 1998;76(3-4):208-14; Richard P et al. Circulation. 2003;107(17):2227-32). This variant was observed to co-segregate with a clinical phenotype in eight relatives in a four-generation family with HCM; however, four additional relatives with this variant in the same family did not exhibit a clinical phenotype suggesting reduced penetrance or variable age of onset (Flavigny J et al. J Mol Med. 1998;76(3-4):208-14). Functional in vitro analyses indicate this variant disturbs Ca2+ sensitivity, thus reducing binding affinity and resulting in decreased cardiac contractile force and function (Szczesna D et al. J Biol Chem. 2001;276(10):7086-92; Roopnarine O. Biophys J. 2003;84(4):2440-9; Szczesna-Cordary D et al. J Biol Chem. 2004;279(5):3535-42; Farman GP et al. J Appl Physiol. 2014;117(12):1471-7). This variant was previously reported in the SNPDatabase as rs104894370. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at