Submissions for variant NM_002474.3(MYH11):c.1732A>G (p.Ile578Val)

gnomAD frequency: 0.00052  dbSNP: rs111936548

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589107	SCV000234810	likely benign	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Invitae	RCV001079118	SCV000285777	likely benign	Aortic aneurysm, familial thoracic 4	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000243852	SCV000318119	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-05-22	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.
Illumina Laboratory Services, Illumina	RCV001079118	SCV000395381	uncertain significance	Aortic aneurysm, familial thoracic 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589107	SCV000697640	benign	not provided	2016-03-29	criteria provided, single submitter	clinical testing	Variant summary: This c.1753A>G variant affects a non-conserved nucleotide, resulting in amino acid change from Ile to Val. 3/3 in-silico tools predict this variant to be benign (SNPs&GO and Mutation Taster not captured here due to low reliability index and p-value, respectively). The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 97/121158 (1/1249), which exceeds the predicted maximum expected allele frequency for a pathogenic MYH11 variant of 1/769230. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, although a reputable clinical laboratory cites the variant as "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
Color Diagnostics, LLC DBA Color Health	RCV000243852	SCV000914153	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-05-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000243852	SCV002042922	benign	Familial thoracic aortic aneurysm and aortic dissection	2019-05-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589107	SCV004564830	likely benign	not provided	2023-02-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003937650	SCV004756231	likely benign	MYH11-related condition	2021-02-09	criteria provided, single submitter	clinical testing	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).