Submissions for variant NM_002474.3(MYH11):c.2893G>T (p.Ala965Ser)

gnomAD frequency: 0.00031  dbSNP: rs113696032

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182501	SCV000234847	likely benign	not provided	2021-02-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234324	SCV000285782	likely benign	Aortic aneurysm, familial thoracic 4	2025-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001178103	SCV000318527	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-02-17	criteria provided, single submitter	clinical testing	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000234324	SCV000744022	likely benign	Aortic aneurysm, familial thoracic 4	2016-05-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000182501	SCV000885769	uncertain significance	not provided	2024-03-20	criteria provided, single submitter	clinical testing	The MYH11 c.2893G>T; p.Ala965Ser variant (rs113696032), to our knowledge, has not been described in the medical literature but is reported in ClinVar (Variation ID: 201058) and observed in the general population at an overall frequency of 0.034% (97/282898 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.401). Due to limited information, the clinical significance of this variant is uncertain at this time.
Illumina Laboratory Services, Illumina	RCV000234324	SCV001276338	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.
Color Diagnostics, LLC DBA Color Health	RCV001178103	SCV001342458	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-10-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000182501	SCV001371352	uncertain significance	not provided	2020-06-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001178103	SCV002042929	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-08-12	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000234324	SCV002495852	uncertain significance	Aortic aneurysm, familial thoracic 4	2021-12-15	criteria provided, single submitter	clinical testing	MYH11 NM_002474.3 exon 23 p.Ala965Ser (c.2893G>T): This variant has not been reported in the literature but is present in 0.06% (41/68042) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-15740155-C-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:201058). Evolutionary conservation for this variant is unclear; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323431	SCV004028857	likely benign	not specified	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.2914G>T (p.Ala972Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251494 control chromosomes. The observed variant frequency is approximately 280 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06). To our knowledge, no occurrence of c.2914G>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 201058). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000234324	SCV000745968	likely benign	Aortic aneurysm, familial thoracic 4	2017-06-06	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751351	SCV005362875	uncertain significance	MYH11-related disorder	2024-08-26	no assertion criteria provided	clinical testing	The MYH11 c.2914G>T variant is predicted to result in the amino acid substitution p.Ala972Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.065% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.