rs149193520
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_000257.4(MYH7):āc.5519T>Cā(p.Met1840Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000416 in 1,611,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. M1840L) has been classified 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.5519T>C | p.Met1840Thr | missense_variant | 37/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.5519T>C | p.Met1840Thr | missense_variant | 36/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.5519T>C | p.Met1840Thr | missense_variant | 37/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000280 AC: 7AN: 249958Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135302
GnomAD4 exome AF: 0.0000445 AC: 65AN: 1459404Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26AN XY: 726150
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74322
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 17, 2023 | This missense variant replaces methionine with threonine at codon 1840 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals in one family affected with non-syndromic congenital heart defects (PMID: 25931334); these individuals also carried a pathogenic variant in the TBX5 gene. This variant has been identified in 9/281334 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 25, 2023 | This missense variant replaces methionine with threonine at codon 1840 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals in one family affected with non-syndromic congenital heart defects (PMID: 25931334); these individuals also carried a pathogenic variant in the TBX5 gene. This variant has been identified in 9/281334 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 specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 10, 2018 | Variant summary: MYH7 c.5519T>C (p.Met1840Thr) results in a non-conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 275678 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5519T>C, has been reported in the literature in two individuals in one family affected with congenital heart defects, co-occurring with the pathogenic variant TBX5 c.709C>T (p.Arg237Trp) (Jia_2015). This report provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 15, 2020 | Has not been previously published in association with MYH7-related disorders to our knowledge; Reported in ClinVar (ClinVar Variant ID# 234383; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23403236) - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1840 of the MYH7 protein (p.Met1840Thr). This variant is present in population databases (rs149193520, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 234383). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 14, 2023 | The p.M1840T variant (also known as c.5519T>C), located in coding exon 35 of the MYH7 gene, results from a T to C substitution at nucleotide position 5519. The methionine at codon 1840 is replaced by threonine, an amino acid with similar properties. This variant co-occurred with a variant in the TBX5 gene in affected individuals from a family with congenital heart defects (Jia Y et al. Am. J. Med. Genet. A, 2015 Aug;167A:1822-9). This variant has also been detected in an exome cohort; however, clinical details were limited (Sapp JC et al. Am. J. Hum. Genet., 2018 09;103:358-366). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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