Submissions for variant NM_002474.3(MYH11):c.3125G>A (p.Arg1042Gln)

gnomAD frequency: 0.00002  dbSNP: rs771297865

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182502	SCV000234848	uncertain significance	not provided	2023-08-07	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); At the protein level, in silico analysis supports that this missense variant has a deleterious effect on protein structure/function; At the mRNA level, in silico analysis supports a deleterious effect on splicing
Invitae	RCV000530492	SCV000641019	uncertain significance	Aortic aneurysm, familial thoracic 4	2022-09-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1049 of the MYH11 protein (p.Arg1049Gln). This variant is present in population databases (rs771297865, gnomAD 0.004%). 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: 201059). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Eurofins Ntd Llc (ga)	RCV000182502	SCV000861394	uncertain significance	not provided	2018-05-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188125	SCV001355099	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1049 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 been reported in an individual affected with Marfan syndrome (DOI: 10.22541/au.158739953.31329162). This variant has been identified in 4/281230 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	RCV000182502	SCV002501373	uncertain significance	not provided	2022-01-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492809	SCV002777469	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2022-04-11	criteria provided, single submitter	clinical testing