Submissions for variant NM_002474.3(MYH11):c.3766A>C (p.Lys1256Gln)

gnomAD frequency: 0.00015  dbSNP: rs149241435

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000253105	SCV000318316	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-10-18	criteria provided, single submitter	clinical testing	The p.K1256Q variant (also known as c.3766A>C), located in coding exon 27 of the MYH11 gene, results from an A to C substitution at nucleotide position 3766. The lysine at codon 1256 is replaced by glutamine, an amino acid with similar properties. This variant has been detected in individuals with thoracic aortic aneurysm and dissection (TAAD) and in TAAD cohorts; however, clinical details were limited and co-occurring variants in other TAAD-related genes were also detected in some cases (Weerakkody R et al. Genet Med, 2018 Nov;20:1414-1422; Li J et al. Mol Genet Genomic Med. 2021 Oct;9(10):e1800; Chen ZR et al. J Thorac Dis, 2021 Jul;13:4008-4022). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Illumina Laboratory Services, Illumina	RCV000471114	SCV000395348	uncertain significance	Aortic aneurysm, familial thoracic 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471114	SCV000543712	likely benign	Aortic aneurysm, familial thoracic 4	2024-12-12	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000253105	SCV000901077	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000253105	SCV000905113	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamine at codon 1263 of the MYH11 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six individuals affected with thoracic aortic aneurysm and dissection (PMID: 29543232, 34422331, 34498425). Two of these individuals also carried a pathogenic variant in the FBN1 gene that could explain the observed phenotype (PMID: 34498425). This variant has also been reported in one individual affected with ischemic stroke, but was also present in multiple healthy control individuals (PMID: 36973604). This variant has been identified in 81/282316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001582893	SCV001811061	likely benign	not provided	2020-10-02	criteria provided, single submitter	clinical testing	Has been previously reported as a variant of uncertain significance in 2 individuals with TAAD in the published literature (Weerakkody et al., 2018).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 263518; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29543232)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000471114	SCV001950108	uncertain significance	Aortic aneurysm, familial thoracic 4	2021-07-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001582893	SCV003800179	uncertain significance	not provided	2022-10-19	criteria provided, single submitter	clinical testing	The MYH11 c.3766A>C; p.Lys1256Gln variant (rs149241435), is reported in the literature in several individuals affected with thoracic aortic aneurysm and dissection (Chen 2021, Weerakkody 2018). However, this variant was reported in two probands with pathogenic variants in FBN1 and the MYH11 variant did not segregate within the two probands’ families, though specific clinical and inheritance information were not provided (Li 2021). This variant is reported in ClinVar (Variation ID: 263518) and is found in the South Asian population with an allele frequency of 0.0751% (23/30,616 alleles, including one homozygote) in the Genome Aggregation Database. The lysine at codon 1256 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.532). While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of the p.Lys1256Gln variant is uncertain at this time. References: Chen ZR et al. Genetic variants in Chinese patients with sporadic Stanford type A aortic dissection. J Thorac Dis. 2021 Jul;13(7):4008-4022. PMID: 34422331. Li J et al. Genetic testing and clinical relevance of patients with thoracic aortic aneurysm and dissection in northwestern China. Mol Genet Genomic Med. 2021 Oct;9(10):e1800. PMID: 34498425. Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422. PMID: 29543232.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001582893	SCV004847587	uncertain significance	not provided	2019-03-21	criteria provided, single submitter	clinical testing	The p.Lys1263Gln variant in MYH11 has been previously reported, but has been identified in 0.03% (39/129118) of European chromosomes in gnomAD, including 1 homozygous South Asian individual. It has been reported in ClinVar (ID 263518). Computational tools predict predict a impact to the protein, though this information is not predictive enough to determine pathogenicity. In summary, although the frequency of this variant suggests that it is benign, additional information is needed to determine its clinical significance. ACMG/AMP criteria applied: PP3
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001582893	SCV001928096	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001582893	SCV001970807	uncertain significance	not provided		no assertion criteria provided	clinical testing