rs369196744
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP2PP3_Strong
The NM_002474.3(MYH11):āc.2496G>Cā(p.Trp832Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_002474.3 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 |
---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.2496G>C | p.Trp832Cys | missense_variant | 20/41 | ENST00000300036.6 | |
MYH11 | NM_001040113.2 | c.2517G>C | p.Trp839Cys | missense_variant | 21/43 | ENST00000452625.7 | |
MYH11 | NM_001040114.2 | c.2517G>C | p.Trp839Cys | missense_variant | 21/42 | ||
MYH11 | NM_022844.3 | c.2496G>C | p.Trp832Cys | missense_variant | 20/42 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.2496G>C | p.Trp832Cys | missense_variant | 20/41 | 1 | NM_002474.3 | P3 | |
MYH11 | ENST00000452625.7 | c.2517G>C | p.Trp839Cys | missense_variant | 21/43 | 1 | NM_001040113.2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251436Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135898
GnomAD4 exome AF: 0.0000623 AC: 91AN: 1461830Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45AN XY: 727218
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74364
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 13, 2023 | This missense variant replaces tryptophan with cysteine at codon 839 of the MYH11 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with Marfan syndrome, who also carried a pathogenic truncation variant in the FBN1 gene (PMID: 25944730). This variant has also been reported in one individual affected with inherited thoracic aortic aneurysm disease, who also carried a pathogenic c.4210+1G>A variant in the FBN1 gene (doi:10.1016/j.hlc.2015.06.677). This variant has been identified in 5/282828 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 | Ambry Genetics | May 31, 2022 | The p.W832C variant (also known as c.2496G>C), located in coding exon 19 of the MYH11 gene, results from a G to C substitution at nucleotide position 2496. The tryptophan at codon 832 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with a frameshift variant in the FBN1 gene in an individual reported to have Marfan syndrome (Wooderchak-Donahue W et al. Am J Med Genet A, 2015 Aug;167A:1747-57). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 26, 2023 | This missense variant replaces tryptophan with cysteine at codon 839 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Marfan syndrome and thoracic aortic aneurysm, who also carried a pathogenic c.4210+1G>A variant in the FBN1 gene (Robertson et al., 2015). This variant has been identified in 5/282828 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 provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2023 | Has been reported in a patient with Marfan syndrome, who also carried a pathogenic variant in the FBN1 gene (Wooderchak-Donahue et al., 2015); 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: 25944730) - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Dec 27, 2021 | - - |
Marfan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 11, 2015 | - - |
Aortic aneurysm, familial thoracic 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2022 | This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 839 of the MYH11 protein (p.Trp839Cys). This variant is present in population databases (rs369196744, gnomAD 0.008%). This missense change has been observed in individual(s) with Marfan syndrome. However this individual also carried a pathogenic FBN1 variant (PMID: 25944730). ClinVar contains an entry for this variant (Variation ID: 180417). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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