Submissions for variant NM_002474.3(MYH11):c.5516C>T (p.Ala1839Val)

gnomAD frequency: 0.00014  dbSNP: rs112948385

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724061	SCV000229950	uncertain significance	not provided	2014-09-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000252424	SCV000319243	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-27	criteria provided, single submitter	clinical testing	The p.A1839V variant (also known as c.5516C>T), located in coding exon 38 of the MYH11 gene, results from a C to T substitution at nucleotide position 5516. The alanine at codon 1839 is replaced by valine, an amino acid with similar properties, and is located in the coiled coil domain. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV000252424	SCV000395207	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000390537	SCV000395208	uncertain significance	Lissencephaly, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000724061	SCV000536457	uncertain significance	not provided	2024-07-15	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21529752)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456952	SCV000543719	likely benign	Aortic aneurysm, familial thoracic 4	2024-01-24	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659928	SCV000781832	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000252424	SCV000904490	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1846 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 60/282598 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.
Illumina Laboratory Services, Illumina	RCV000456952	SCV001274136	uncertain significance	Aortic aneurysm, familial thoracic 4	2018-01-12	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.
PreventionGenetics, part of Exact Sciences	RCV003407656	SCV004115299	uncertain significance	MYH11-related disorder	2023-03-09	criteria provided, single submitter	clinical testing	The MYH11 c.5537C>T variant is predicted to result in the amino acid substitution p.Ala1846Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.087% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-15809118-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000252424	SCV004239429	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724061	SCV005050315	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	MYH11: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586598	SCV005075965	uncertain significance	not specified	2024-04-01	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.5537C>T (p.Ala1846Val) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of 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 0.00022 in 251200 control chromosomes. The observed variant frequency is approximately 178-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), suggesting that the variant could be benign. To our knowledge, no occurrence of c.5537C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 197069). Based on the evidence outlined above, the variant was classified as uncertain significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000724061	SCV000925174	uncertain significance	not provided	2016-07-22	no assertion criteria provided	provider interpretation	p.Ala1846Val (c.5537C>T) in the MYH11 gene (NM_001040113.1) Given the lack of case data and allele frequency in ExAC we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). MYH11 has been associated with autosomal dominant thoracic aortic aneurysms and dissection. Per the lab report and our own searches, the variant has not been reported in individuals with aneurysms and dissections. The variant was reported online in 26 of 60536 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 20th, 2016). Specifically, the variant was observed in Latinos, Europeans, East Asians, and Africans. The highest allele frequency was in the "other" group (0.002217). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.