NM_000257.4:c.3138G>A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PP2PP3_ModerateBS1_Supporting
The NM_000257.4(MYH7):c.3138G>A(p.Met1046Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,198 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 (★★).
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251482Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727242
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152310Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74476
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Met1046Il e variant in MYH7 has not been previously reported in individuals with cardiomyo pathy, but has been identified in 3/66740 European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201195256). Me thionine (Met) at position 1046 is highly conserved in mammals and is moderately conserved across evolutionarily distant species and the change to isoleucine (I le) was predicted to be pathogenic using a computational tool clinically validat ed by our laboratory. This tool's pathogenic prediction is estimated to be corre ct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Met1046Ile variant is unce rtain. -
Dilated cardiomyopathy 1S Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Cardiomyopathy Uncertain:1
Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the neck and hinge region (S2 domain) of the MYH7 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been reported in an individual affected with hypertrophic cardiomyopathy in a public database (www.cardiodb.org). This variant has also been identified in 3/246258 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. -
Hypertrophic cardiomyopathy Uncertain:1
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1046 of the MYH7 protein (p.Met1046Ile). This variant is present in population databases (rs201195256, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 228907). 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 MYH7 protein function with a positive predictive value of 95%. 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