Submissions for variant NM_002474.3(MYH11):c.1202T>C (p.Ile401Thr)

dbSNP: rs773998062

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182553	SCV000234901	uncertain significance	not provided	2023-09-06	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455159	SCV000539831	uncertain significance	not specified	2016-10-27	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been reported in affected patients. It has a Max MAF in ExAC of 0.001%. It is classified in ClinVar as Likely Path by GeneDx (1 star) though the provided interpretation suggests VUS.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170345	SCV001332917	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-01-22	criteria provided, single submitter	clinical testing
Invitae	RCV001208836	SCV001380245	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 408 of the MYH11 protein (p.Ile408Thr). This variant is present in population databases (rs773998062, gnomAD 0.003%). 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: 201107). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH11 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001170345	SCV001735915	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 408 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH11-related disorders in the literature. This variant has been identified in 3/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000182553	SCV002501639	uncertain significance	not provided	2021-07-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001170345	SCV002650171	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-12	criteria provided, single submitter	clinical testing	The p.I401T variant (also known as c.1202T>C), located in coding exon 10 of the MYH11 gene, results from a T to C substitution at nucleotide position 1202. The isoleucine at codon 401 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485206	SCV002787133	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-10-01	criteria provided, single submitter	clinical testing