ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.5273G>A (p.Arg1758Gln) (rs142546324)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182528 SCV000234875 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH11 gene. The R1758Q variant has been reported in association with TAAD (Zhu et al., 2006; Poninska et al., 2016). However, this variant was present on the same allele as a downstream IVS32+1 G>T pathogenic variant in 11 affected members, and one unaffected individual, in one family (Zhu et al., 2006). The R1758Q variant is observed in 47/126414 (0.04%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Nevertheless, the R1758Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000148691 SCV000543699 uncertain significance Aortic aneurysm, familial thoracic 4 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1765 of the MYH11 protein (p.Arg1765Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs142546324, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in a family with thoracic aortic aneurysms and dissection (TAAD) (PMID: 16444274). However, in all of the affected individuals, a canonical splice variant was also identified in MYH11, which suggests that this c.5294G>A variant was not the primary cause of disease. It was also observed in an unrelated individual with TAAD (PMID: 27146836). This variant is also known as p.Arg1758Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 161316). Clinvar also contains an entry for the haplotype that segregated with the TAAD phenotype in PMID: 16444274 (Variation ID: 14131). 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, but these predictions have not been confirmed by published functional studies. 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.
Color Health, Inc RCV000611174 SCV000913866 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174812 SCV001338163 likely benign not specified 2020-02-17 criteria provided, single submitter clinical testing Variant summary: MYH11 c.5294G>A (p.Arg1765Gln) results in a conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 247716 control chromosomes, predominantly at a frequency of 0.00035 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 280 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. c.5294G>A has been reported in the literature in individuals with different cardiac conditions (Zhu_2006, Poninska_2016, Ravindra_2016, Gillis_2017, Weerakkody_2018). These reports do not provide unequivocal conclusions about association of the variant with Aortopathy. Co-occurrence with a pathogenic variant has been reported (MYH11 c.4578+1G>T, Zhu_2006), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
CSER _CC_NCGL, University of Washington RCV000148691 SCV000190418 likely benign Aortic aneurysm, familial thoracic 4 2014-06-01 no assertion criteria provided research
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000611174 SCV000731237 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection no assertion criteria provided research

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