Submissions for variant NM_002474.3(MYH11):c.5596G>A (p.Glu1866Lys)

gnomAD frequency: 0.00003  dbSNP: rs148743922

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000247569	SCV000319368	uncertain significance	Cardiovascular phenotype	2014-11-25	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553332	SCV000641075	uncertain significance	Aortic aneurysm, familial thoracic 4	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1873 of the MYH11 protein (p.Glu1873Lys). This variant is present in population databases (rs148743922, gnomAD 0.03%). 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: 263884). 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.
Color Diagnostics, LLC DBA Color Health	RCV000777865	SCV000913871	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1873 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 11/282646 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.
GeneDx	RCV001753734	SCV002005181	uncertain significance	not provided	2024-09-05	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign in association with a MYH11-related disorder to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21529752, 35982159, 33057194)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767200	SCV005381179	uncertain significance	not specified	2024-08-13	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.5617G>A (p.Glu1873Lys) results in a conservative amino acid change in 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 4e-05 in 251258 control chromosomes. The observed variant frequency is approximately 31.84 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), however the frequency is within pathogenic range for a hypothetical variant associated with the recessive MYH11 phenotype, Megacystis-microcolon-intestinal hypoperistalsis syndrome. To our knowledge, no occurrence of c.5617G>A in individuals affected with MYH11-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 263884). Based on the evidence outlined above, the variant was classified as uncertain significance.