Submissions for variant NM_002474.3(MYH11):c.4728C>G (p.Phe1576Leu)

gnomAD frequency: 0.00001  dbSNP: rs765435868

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001185564	SCV000739208	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-05-25	criteria provided, single submitter	clinical testing	The p.F1576L variant (also known as c.4728C>G), located in coding exon 32 of the MYH11 gene, results from a C to G substitution at nucleotide position 4728. The phenylalanine at codon 1576 is replaced by leucine, an amino acid with highly similar properties. Based on data from ExAC (Exome Aggregation Consortium), the G allele has an overall frequency less than 0.01% (2/106205). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6497 samples (12994 alleles) with coverage at this position. 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 variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706681	SCV000835748	uncertain significance	Aortic aneurysm, familial thoracic 4	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1583 of the MYH11 protein (p.Phe1583Leu). This variant is present in population databases (rs765435868, 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: 519938). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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	RCV001185564	SCV001351813	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-09	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 1583 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 MYH11-related disorders in the literature. This variant has been identified in 2/251472 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.
All of Us Research Program, National Institutes of Health	RCV001185564	SCV004821186	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 1583 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 2/251472 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.
GeneDx	RCV004721481	SCV005327320	uncertain significance	not provided	2024-01-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge