Submissions for variant NM_002474.3(MYH11):c.115C>A (p.Pro39Thr)

dbSNP: rs761131497

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001181172	SCV001346268	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 39 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 MYH11-related disorders in the literature. This variant has been identified in 1/250726 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002559777	SCV003263657	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 39 of the MYH11 protein (p.Pro39Thr). This variant is present in population databases (rs761131497, gnomAD 0.0009%). 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: 921623). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
All of Us Research Program, National Institutes of Health	RCV001181172	SCV004816895	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-07-20	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the N-terminal SH3-like domain of the MYH11 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/245494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Ambry Genetics	RCV001181172	SCV005019236	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-12	criteria provided, single submitter	clinical testing	The p.P39T variant (also known as c.115C>A), located in coding exon 1 of the MYH11 gene, results from a C to A substitution at nucleotide position 115. The proline at codon 39 is replaced by threonine, an amino acid with highly 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.