Submissions for variant NM_002474.3(MYH11):c.4747C>T (p.Arg1583Trp)

gnomAD frequency: 0.00004  dbSNP: rs777170587

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001181545	SCV000739181	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-08-03	criteria provided, single submitter	clinical testing	The p.R1583W variant (also known as c.4747C>T), located in coding exon 32 of the MYH11 gene, results from a C to T substitution at nucleotide position 4747. The arginine at codon 1583 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the coiled coil domain. An alternate amino acid substitution at this position, p.R1583Q was reported (as p.R1590Q) in two family members with thoracic aortic aneurysms (Bee KJ et al. Circ Cardiovasc Genet, 2012 Dec;5:621-9). This amino acid position is well conserved in available vertebrate species. 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	RCV000765254	SCV000896504	uncertain significance	Aortic aneurysm, familial thoracic 4	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000765254	SCV000959295	uncertain significance	Aortic aneurysm, familial thoracic 4	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1590 of the MYH11 protein (p.Arg1590Trp). This variant is present in population databases (rs777170587, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of MYH11-related conditions (PMID: 29543232). This variant is also known as c.4747C>T (p.Arg1583Trp). ClinVar contains an entry for this variant (Variation ID: 519925). 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 80%. This variant disrupts the p.Arg1590 amino acid residue in MYH11. Other variant(s) that disrupt this residue have been observed in individuals with MYH11-related conditions (PMID: 23099432, 29543232), which suggests that this may be a clinically significant amino acid residue. 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	RCV001181545	SCV001346719	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1590 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 9/251414 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508774	SCV001715136	uncertain significance	not provided	2020-09-25	criteria provided, single submitter	clinical testing
GeneDx	RCV001508774	SCV003837381	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing	Identified in patients with TAAD referred for genetic testing at GeneDx and in the published literature (PMID: 29543232); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30202019, 29543232)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001181545	SCV004239423	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-30	criteria provided, single submitter	clinical testing