Submissions for variant NM_002474.3(MYH11):c.4834C>T (p.Arg1612Cys)

gnomAD frequency: 0.00002  dbSNP: rs748356212

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478064	SCV000573719	uncertain significance	not provided	2017-02-24	criteria provided, single submitter	clinical testing	The R1612C variant in the MYH11 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1612C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1612C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1612C as a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001805103	SCV002053353	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1619 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 5/251382 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.
Ambry Genetics	RCV001805103	SCV002635108	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-04-21	criteria provided, single submitter	clinical testing	The p.R1612C variant (also known as c.4834C>T), located in coding exon 33 of the MYH11 gene, results from a C to T substitution at nucleotide position 4834. The arginine at codon 1612 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002475955	SCV002777457	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-08-26	criteria provided, single submitter	clinical testing
Invitae	RCV002526963	SCV003470241	uncertain significance	Aortic aneurysm, familial thoracic 4	2022-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1619 of the MYH11 protein (p.Arg1619Cys). This variant is present in population databases (rs748356212, gnomAD 0.01%). 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: 423952). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.