Submissions for variant NM_002474.3(MYH11):c.4403C>T (p.Ala1468Val)

gnomAD frequency: 0.00004  dbSNP: rs370240337

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182520	SCV000234866	uncertain significance	not provided	2020-02-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics	RCV000769664	SCV000739183	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-03-01	criteria provided, single submitter	clinical testing	The p.A1468V variant (also known as c.4403C>T), located in coding exon 31 of the MYH11 gene, results from a C to T substitution at nucleotide position 4403. The alanine at codon 1468 is replaced by valine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs370240337. Based on data from ExAC, the T allele has an overall frequency of approximately 0.004% (5/121410). The highest observed frequency was 0.01% (1/8654) of East Asian alleles (Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [Accessed March 1, 2016]). Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.01% (1/12994) total alleles studied and 0.01% (1/8600) European American alleles. This amino acid position is highly 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 variant remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769664	SCV000901072	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769664	SCV001350482	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1475 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 MYH11-related disorders in the literature. This variant has been identified in 11/251472 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182520	SCV001715137	uncertain significance	not provided	2021-03-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492811	SCV002778503	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-08-31	criteria provided, single submitter	clinical testing
Invitae	RCV002516857	SCV003021454	uncertain significance	Aortic aneurysm, familial thoracic 4	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1475 of the MYH11 protein (p.Ala1475Val). This variant is present in population databases (rs370240337, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical suspicion of thoracic aortic aneurysms and dissections (PMID: 34498425). This variant is also known as p.Ala1468Val. ClinVar contains an entry for this variant (Variation ID: 201076). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000182520	SCV001807926	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000182520	SCV001970124	uncertain significance	not provided		no assertion criteria provided	clinical testing