14-23383233-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP2PP3_Strong
The NM_002471.4(MYH6):c.5653G>A(p.Glu1885Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,577,432 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1885G) has been classified as Uncertain significance.
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.5653G>A | p.Glu1885Lys | missense_variant | 37/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.5653G>A | p.Glu1885Lys | missense_variant | 37/39 | 5 | NM_002471.4 | P1 | |
MYH6 | ENST00000651452.1 | n.880G>A | non_coding_transcript_exon_variant | 1/3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000133 AC: 2AN: 149878Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251416Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135886
GnomAD4 exome AF: 0.0000119 AC: 17AN: 1427554Hom.: 0 Cov.: 35 AF XY: 0.00000704 AC XY: 5AN XY: 710074
GnomAD4 genome ? AF: 0.0000133 AC: 2AN: 149878Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1AN XY: 73038
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 01, 2023 | Reported in a patient with congenital heart disease who harbored an additional MYH6 variant in trans (Preuss et al., 2016); 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: 27760138, 26284702, 35779862, 32233023) - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2020 | Variant summary: MYH6 c.5653G>A (p.Glu1885Lys) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251416 control chromosomes (gnomAD). c.5653G>A has been reported to segregate with Wolff Parkinson White syndrome in a family (Bowles_2015). The variant was also reported in an individual who died of hypoplastic left heart syndrome and her unaffected mother. The patient was however, compound heterozygous for the variant of interest and another MYH6 variant (Preuss_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH6 protein function. ClinVar contains an entry for this variant (Variation ID: 537966). This missense change has been observed in individual(s) with a MYH6-related disease and Wolff–Parkinson–White syndrome (PMID: 26284702, 27760138). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs760353963, gnomAD 0.006%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1885 of the MYH6 protein (p.Glu1885Lys). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 2023 | The p.E1885K variant (also known as c.5653G>A), located in coding exon 35 of the MYH6 gene, results from a G to A substitution at nucleotide position 5653. The glutamic acid at codon 1885 is replaced by lysine, an amino acid with similar properties. This alteration has been reported to segregate in a family with Wolff-Parkinson-White syndrome (Bowles NE et al. Am J Med Genet A, 2015 Dec;167A:2975-84). This alteration was also reported as a compound heterozygote in an infant with hypoplastic left heart syndrome (Preuss C et al. PLoS Genet, 2016 Oct;12:e1006335). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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