rs201831933
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_002474.3(MYH11):c.3791T>C(p.Leu1264Pro) 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. 13/21 in silico tools predict a damaging 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. L1264V) has been classified as Uncertain significance.
Frequency
Consequence
NM_002474.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.3791T>C | p.Leu1264Pro | missense_variant | 28/41 | ENST00000300036.6 | |
MYH11 | NM_001040113.2 | c.3812T>C | p.Leu1271Pro | missense_variant | 29/43 | ENST00000452625.7 | |
MYH11 | NM_001040114.2 | c.3812T>C | p.Leu1271Pro | missense_variant | 29/42 | ||
MYH11 | NM_022844.3 | c.3791T>C | p.Leu1264Pro | missense_variant | 28/42 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.3791T>C | p.Leu1264Pro | missense_variant | 28/41 | 1 | NM_002474.3 | P3 | |
MYH11 | ENST00000452625.7 | c.3812T>C | p.Leu1271Pro | missense_variant | 29/43 | 1 | NM_001040113.2 | ||
ENST00000574212.1 | n.242A>G | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Aortic aneurysm, familial thoracic 4 Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 22, 2021 | 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. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed to segregate with thoracic aortic aneurysm and dissection in families (PMID: 17666408, 27081537) and has been observed in an individual affected with this disease (Invitae). This variant is also known as L1264P in the literature. ClinVar contains an entry for this variant (Variation ID: 88953, 440783). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 1271 of the MYH11 protein (p.Leu1271Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2024 | The p.L1264P pathogenic mutation (also known as c.3791T>C), located in coding exon 27 of the MYH11 gene, results from a T to C substitution at nucleotide position 3791. The leucine at codon 1264 is replaced by proline, an amino acid with similar properties. This variant has segregated with disease in a family with thoracic aortic aneurysm and dissection (TAAD) and patent ductus arteriosus (PDA) and was suggested to be in linkage disequilibrium with a second MYH11 missense variant, both located in the coiled-coil domain. The p.L1264P alteration was predicted to introduce a helix breaking residue (proline), disrupting the coiled-coil formation (Pannu H et al. Hum Mol Genet. 2007;16(20):2453-2462). This variant has also segregated with disease in a second family with TAAD (Takeda N et al. Hum Genome Var. 2015 Aug;2:15028). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of MYH11-related thoracic aortic aneurysm and dissection; however, its clinical significance for MYH11-related megacystis-microcolon-intestinal hypoperistalsis syndrome is unclear. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 28, 2015 | p.Leu1264Pro (CTG>CCG): c.3791 T>C in exon 28 of the MYH11 gene (NM_002474.2)The L1264P mutation in the MYH11 gene has been reported in one family in association with TAAD and patent ductus arteriosus (PDA) (Pannu et al., 2007). L1264P was identified in three family members with history of PDA, aortic aneurysm/dissection and was absent from 360 control chromosomes (Pannu et al, 2007). The L1264P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts L1264P is probably damaging the protein structure/function. Located in the regulatory region of the MYH11 gene, the presence of L1264P significantly decreases the probability of coiled-coil formation in the normal protein sequence (Pannu et al., 2007). Lastly, the L1264P mutation was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, L1264P in the MYH11 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at