ClinVar Miner

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

gnomAD frequency: 0.00029  dbSNP: rs144244239
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Total submissions: 8
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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 2024-01-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV001180812 SCV000318102 likely benign Familial thoracic aortic aneurysm and aortic dissection 2020-07-02 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000182554 SCV000919817 likely benign not specified 2023-08-28 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 251476 control chromosomes (gnomAD). The observed variant frequency is approximately 165 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) and suspected of thoracic artery aneurysm and dissection (Bharadwaj_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35372177, 28855619, 26017485). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and benign/likely benign (n=5). 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 Diagnostics, LLC DBA Color Health RCV001180812 SCV001345835 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-05-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 508 of the MYH11 protein. Computational prediction tools and conservation analyses suggest that this variant may impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 63/282888 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and is fairly common in the East Asian population (22/19954 chromosomes; 0.11%). This variant allele frequency is greater than expected for the MYH11-related disorder based on prevalence, penetrance, and genetic heterogeneity. Based on available evidence, this variant is classified as Likely Benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000182554 SCV001433257 benign not specified 2019-08-30 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001180812 SCV004239404 likely benign Familial thoracic aortic aneurysm and aortic dissection 2023-04-27 criteria provided, single submitter clinical testing

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