Submissions for variant NM_002474.3(MYH11):c.5176G>A (p.Ala1726Thr)

gnomAD frequency: 0.00005  dbSNP: rs376154041

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000698929	SCV000827620	uncertain significance	Aortic aneurysm, familial thoracic 4	2022-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1733 of the MYH11 protein (p.Ala1733Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 375862). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000762208	SCV000892482	uncertain significance	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188909	SCV001356086	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-11-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001188909	SCV002643701	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-12-18	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.
GeneDx	RCV000762208	SCV002762286	uncertain significance	not provided	2022-06-14	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
CSER _CC_NCGL, University of Washington	RCV001796029	SCV000503547	uncertain significance	Congenital aneurysm of ascending aorta	2016-08-01	no assertion criteria provided	research	Found in patient having exome sequencing for an unrelated indication. No known history of thoracic aortic aneurysm(s).
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000762208	SCV001797688	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000762208	SCV001928221	likely benign	not provided		no assertion criteria provided	clinical testing