Submissions for variant NM_002474.3(MYH11):c.3619G>A (p.Glu1207Lys)

gnomAD frequency: 0.00001  dbSNP: rs371831822

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000246055	SCV000319127	uncertain significance	Cardiovascular phenotype	2013-09-16	criteria provided, single submitter	clinical testing	The p.E1207K variant (also known as c.3619G>A) is located in coding exon 26 of the MYH11 gene. This alteration results from a G to A substitution at nucleotide position 3619. The glutamic acid at codon 1207 is replaced by lysine, an amino acid with some similar properties. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.01% (1/12,994), having been observed in 0.01% (1/8600) of European American alleles and in none of 4394 African American alleles. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging by PolyPhen but tolerated by SIFT in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473967	SCV000543701	uncertain significance	Aortic aneurysm, familial thoracic 4	2025-01-27	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 1214 of the MYH11 protein (p.Glu1214Lys). This variant is present in population databases (rs371831822, gnomAD 0.003%). 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: 263772). 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	RCV001184000	SCV001349868	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1214 of the MYH11 protein. Computational prediction suggests that this variant may have a 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 cardiovascular disorders in the literature. This variant has been identified in 3/251464 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223200	SCV002501802	uncertain significance	not provided	2021-07-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002223200	SCV004564573	uncertain significance	not provided	2023-11-07	criteria provided, single submitter	clinical testing	The MYH11 c.3619G>A; p.Glu1207Lys variant (rs371831822), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 263772). This variant is found in the general population with an overall allele frequency of 0.003% (3/113,740 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.88). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time.
All of Us Research Program, National Institutes of Health	RCV001184000	SCV004821314	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1214 of the MYH11 protein. Computational prediction suggests that this variant may have a 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 cardiovascular disorders in the literature. This variant has been identified in 3/251464 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	RCV002223200	SCV005687895	uncertain significance	not provided	2024-08-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge