Submissions for variant NM_002474.3(MYH11):c.5441C>T (p.Ser1814Phe)

gnomAD frequency: 0.00001  dbSNP: rs759033733

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756381	SCV000884176	uncertain significance	not provided	2017-12-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177358	SCV001341556	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 1821 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 21/251390 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.
Invitae	RCV001219857	SCV001391816	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1821 of the MYH11 protein (p.Ser1821Phe). This variant is present in population databases (rs759033733, gnomAD 0.02%). 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: 618231). 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.
GeneDx	RCV000756381	SCV001790889	uncertain significance	not provided	2018-12-27	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Ambry Genetics	RCV001177358	SCV002652265	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-05-28	criteria provided, single submitter	clinical testing	The p.S1814F variant (also known as c.5441C>T), located in coding exon 37 of the MYH11 gene, results from a C to T substitution at nucleotide position 5441. The serine at codon 1814 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485955	SCV002800184	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-09-07	criteria provided, single submitter	clinical testing