Submissions for variant NM_002474.3(MYH11):c.3104T>C (p.Met1035Thr)

gnomAD frequency: 0.00003  dbSNP: rs557463209

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001182525	SCV001347992	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1042 of the MYH11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 15/251216 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193456	SCV001362296	likely benign	not specified	2019-03-04	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.3125T>C (p.Met1042Thr) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 246040 control chromosomes, predominantly at a frequency of 0.00042 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 336 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.3125T>C in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV001876059	SCV002109160	uncertain significance	Aortic aneurysm, familial thoracic 4	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1042 of the MYH11 protein (p.Met1042Thr). This variant is present in population databases (rs557463209, 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: 922441). 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.
Ambry Genetics	RCV001182525	SCV002605979	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-08-02	criteria provided, single submitter	clinical testing	The p.M1035T variant (also known as c.3104T>C), located in coding exon 23 of the MYH11 gene, results from a T to C substitution at nucleotide position 3104. The methionine at codon 1035 is replaced by threonine, an amino acid with similar 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.
PreventionGenetics, part of Exact Sciences	RCV003918763	SCV004729407	uncertain significance	MYH11-related condition	2024-02-16	criteria provided, single submitter	clinical testing	The MYH11 c.3125T>C variant is predicted to result in the amino acid substitution p.Met1042Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.043% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.