Submissions for variant NM_002474.3(MYH11):c.508G>A (p.Glu170Lys)

gnomAD frequency: 0.00004  dbSNP: rs766315580

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182544	SCV000234892	uncertain significance	not provided	2014-05-03	criteria provided, single submitter	clinical testing	p.Glu170Lys (GAG>AAG): c.508 G>A in exon 4 of the MYH11 gene (NM_002474.2). A variant of unknown significance has been identified in the MYH11 gene. The E170K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The E170K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E170K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense mutations affecting nearby residues have been reported in association with TAAD, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in TAAD panel(s).
Blueprint Genetics	RCV000182544	SCV000927615	uncertain significance	not provided	2018-04-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818506	SCV000959124	uncertain significance	Aortic aneurysm, familial thoracic 4	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 170 of the MYH11 protein (p.Glu170Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. 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: 201099). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	RCV003996720	SCV004833464	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 170 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 MYH11-related disorders in the literature. This variant has been identified in 12/281902 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.