ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.1502G>A (p.Arg501His) (rs144244239)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182554 SCV000234902 likely benign not specified 2016-10-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001001499 SCV000285774 likely benign Aortic aneurysm, familial thoracic 4 2020-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000243227 SCV000318102 likely benign Cardiovascular phenotype 2020-07-02 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000182554 SCV000919817 likely benign not specified 2018-04-30 criteria provided, single submitter clinical testing Variant summary: MYH11 c.1523G>A (p.Arg508His) 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 0.00021 in 277254 control chromosomes (gnomAD). The observed variant frequency is approximately 170 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 benign. The variant, c.1523G>A, has been reported in the literature in individuals affected with Aortopathy (Fang_2017, vandeLuijtgaarden_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001499 SCV001158794 uncertain significance Aortic aneurysm, familial thoracic 4 2018-09-03 criteria provided, single submitter clinical testing The MYH11 c.1502G>A; p.Arg501His variant (rs144244239) is reported in the medical literature in at least two individuals with abdominal aortic aneurysm (Fang 2017, van de Luijtgaarden 2015). The variant is reported as uncertain by one source and likely benign by two sources, but with insufficient evidence to independently analyze (Variation ID: 201108). This variant is found in the general population with an overall allele frequency of 0.02% (59/277254 alleles) in the Genome Aggregation Database. The arginine at codon 501 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict this variant is deleterious. Considering available information, this variant is classified as uncertain. Pathogenic MYH11 variants are inherited in an autosomal dominant manner, and are associated with familial thoracic aortic aneurysm 4 (MIM: 132900). References: Fang M et al. Identification of Novel Clinically Relevant Variants in 70 Southern Chinese patients with Thoracic Aortic Aneurysm and Dissection by Next-generation Sequencing. Sci Rep. 2017 Aug 30;7(1):10035. van de Luijtgaarden et al. First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm. Hum Genet. 2015 Aug;134(8):881-93.
Color Health, Inc RCV001180812 SCV001345835 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-05-16 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000182554 SCV001433257 benign not specified 2019-08-30 criteria provided, single submitter clinical testing

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