Submissions for variant NM_002474.3(MYH11):c.5584C>T (p.Arg1862Cys)

gnomAD frequency: 0.00002  dbSNP: rs757542362

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001191151	SCV001358856	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1869 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 cardiovascular disorders in the literature. This variant has been identified in 10/251332 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.
Fulgent Genetics, Fulgent Genetics	RCV002497669	SCV002813495	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-11-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002559185	SCV003295044	uncertain significance	Aortic aneurysm, familial thoracic 4	2022-09-16	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 1869 of the MYH11 protein (p.Arg1869Cys). This variant is present in population databases (rs757542362, gnomAD 0.04%). 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: 927691). 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. 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.
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV002559185	SCV004363574	uncertain significance	Aortic aneurysm, familial thoracic 4	2023-11-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001191151	SCV004815511	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1869 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 cardiovascular disorders in the literature. This variant has been identified in 10/251332 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	RCV001191151	SCV005018992	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-06	criteria provided, single submitter	clinical testing	The p.R1862C variant (also known as c.5584C>T), located in coding exon 38 of the MYH11 gene, results from a C to T substitution at nucleotide position 5584. The arginine at codon 1862 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.