chr12-110919117-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_000432.4(MYL2):c.80A>G(p.Gln27Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q27H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000432.4 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 | UniProt |
---|---|---|---|---|---|---|---|
MYL2 | NM_000432.4 | c.80A>G | p.Gln27Arg | missense_variant | 2/7 | ENST00000228841.15 | |
MYL2 | NM_001406745.1 | c.80A>G | p.Gln27Arg | missense_variant | 2/6 | ||
MYL2 | NM_001406916.1 | c.23A>G | p.Gln8Arg | missense_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYL2 | ENST00000228841.15 | c.80A>G | p.Gln27Arg | missense_variant | 2/7 | 1 | NM_000432.4 | P1 | |
MYL2 | ENST00000548438.1 | c.80A>G | p.Gln27Arg | missense_variant | 2/6 | 3 | |||
MYL2 | ENST00000663220.1 | c.23A>G | p.Gln8Arg | missense_variant | 2/7 | ||||
MYL2 | ENST00000546404.1 | c.80A>G | p.Gln27Arg | missense_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Primary familial hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 10, 2012 | The Gln27Arg variant in MYL2 has not been reported in the literature, but has be en identified in one individual with HCM previously tested by our laboratory and segregated with disease in one affected relative in this family (LMM unpublishe d data). This variant has also not been identified in large and broad European A merican and African American populations by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS); this low frequency is consistent with a disea se causing role but insufficient to establish this with confidence. Glutamine (G ln) at position 27 is highly conserved in mammals and across evolutionarily dist ant species and the change to Arginine (Arg) was predicted to be pathogenic usin g a computational tool clinically validated by our laboratory. This tool's patho genic prediction is estimated to be correct 94% of the time (Jordan 2011). In su mmary, this variant is likely to be pathogenic, though additional studies are re quired to fully establish its clinical significance. - |
Hypertrophic cardiomyopathy 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 25, 2022 | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 27 of the MYL2 protein (p.Gln27Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43481). 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: "Possibly 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at