16-15778831-G-A
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2
The NM_002474.3(MYH11):c.739C>T(p.Arg247Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,614,024 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002474.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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MYH11 | NM_002474.3 | c.739C>T | p.Arg247Cys | missense_variant | Exon 7 of 41 | ENST00000300036.6 | NP_002465.1 | |
MYH11 | NM_001040113.2 | c.760C>T | p.Arg254Cys | missense_variant | Exon 8 of 43 | ENST00000452625.7 | NP_001035202.1 | |
MYH11 | NM_001040114.2 | c.760C>T | p.Arg254Cys | missense_variant | Exon 8 of 42 | NP_001035203.1 | ||
MYH11 | NM_022844.3 | c.739C>T | p.Arg247Cys | missense_variant | Exon 7 of 42 | NP_074035.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MYH11 | ENST00000300036.6 | c.739C>T | p.Arg247Cys | missense_variant | Exon 7 of 41 | 1 | NM_002474.3 | ENSP00000300036.5 | ||
MYH11 | ENST00000452625.7 | c.760C>T | p.Arg254Cys | missense_variant | Exon 8 of 43 | 1 | NM_001040113.2 | ENSP00000407821.2 |
Frequencies
GnomAD3 genomes AF: 0.00165 AC: 251AN: 152030Hom.: 1 Cov.: 31
GnomAD3 exomes AF: 0.00174 AC: 438AN: 251466Hom.: 1 AF XY: 0.00169 AC XY: 229AN XY: 135902
GnomAD4 exome AF: 0.00262 AC: 3833AN: 1461874Hom.: 11 Cov.: 32 AF XY: 0.00250 AC XY: 1817AN XY: 727234
GnomAD4 genome AF: 0.00164 AC: 250AN: 152150Hom.: 1 Cov.: 31 AF XY: 0.00140 AC XY: 104AN XY: 74368
ClinVar
Submissions by phenotype
Aortic aneurysm, familial thoracic 4 Uncertain:1Benign:6
MYH11 NM_002474.2 exon 7 p.Arg247Cys (c.739C>T): This variant has been reported in the literature (also referred to as p.Arg254Cys) in at least one individual with abdominal aortic aneurysm, segregating with disease in one affected family member (Van de Luijtgaarden 2015 PMID:26017485). This variant is present in 0.3% (393/129162) of European alleles in the Genome Aggregation Database, including 2 homozygotes (http://gnomad.broadinstitute.org/variant/16-15872688-G-A). This variant is also present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:161317). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Kuang 2012 PMID: 22511748; Bellini 2015 PMID: 25433566). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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Familial thoracic aortic aneurysm and aortic dissection Benign:4
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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Benign:4
This variant is associated with the following publications: (PMID: 22968129, 16444274, 25407000, 24337657, 10854329, 22511748, 25433566, 26893369, 27879251, 27153395, 29494672, 17956658, 17666408, 14722581, 10199307, 7923625, 26792327, 25424711, 24676022, 27418595, 26017485, 25637381, 26332594, 27535533, 29961567, 32220188, 32068640) -
MYH11: PP3, BS2 -
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not specified Benign:2
Variant summary: MYH11 c.760C>T (p.Arg254Cys, also known as c.739C>T/p.Arg247Cys) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 282840 control chromosomes, predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2400 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.760C>T, has been reported in the literature in at least one family with 2 affected individuals (Van de Luijtgaarden_2015), and in patients with aortic disease and no family history (Kuang_2012). These reports however do not provide unequivocal conclusions about association of the variant with Aortopathy. Publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the p.Arg247Cys substitution decreases the ATPase activity (actin-activated), and the rate of actin filament sliding, and in a knock-in mouse model the mutant aorta displayed a decreased contractile response, but there was no overall vascular phenotype under normal conditions in either homozygous or heterozygous mice (Kuang_2012, Huang_2018). However, the homozygous mutant knock-in mice were more vulnerable to alterations in hemodynamic loading (Bellini_2015), or developed aortic dilation when crossed with the ACTA2 +/- mice, indicating that two variants not known to cause disease may lead to aortic enlargement in combination (Kwartler_2018). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign 7x, VUS 2x). Based on the evidence outlined above, the variant is unlikely to cause familial thoracic aortic disease, but more evidence is required to determine if it might represent a low penetrance risk variant, therefore it was classified as likely benign. -
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.3% European; ClinVar: 2 VUS, 1 LB -
Loeys-Dietz syndrome Uncertain:1
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Connective tissue disorder Uncertain:1
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Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Uncertain:1
MYH11 NM_002474.2 exon 7 p.Arg247Cys (c.739C>T): This variant has been reported in the literature (also referred to as p.Arg254Cys) in at least one individual with abdominal aortic aneurysm, segregating with disease in one affected family member (Van de Luijtgaarden 2015 PMID:26017485). This variant is present in 0.3% (393/129162) of European alleles in the Genome Aggregation Database, including 2 homozygotes (http://gnomad.broadinstitute.org/variant/16-15872688-G-A). This variant is also present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:161317). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Kuang 2012 PMID: 22511748; Bellini 2015 PMID: 25433566). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
MYH11-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Altered myosin contractile function Benign:1
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Congenital aneurysm of ascending aorta;C1851504:Aortic aneurysm, familial thoracic 4 Other:1
Variant interpretted as Uncertain significance and reported on 03/28/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at