Submissions for variant NM_002474.3(MYH11):c.1574C>T (p.Pro525Leu)

gnomAD frequency: 0.00001  dbSNP: rs750288554

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230642	SCV000285775	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 532 of the MYH11 protein (p.Pro532Leu). This variant is present in population databases (rs750288554, gnomAD 0.01%). 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: 238257). 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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000230642	SCV000781807	uncertain significance	Aortic aneurysm, familial thoracic 4	2016-11-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000230642	SCV001274871	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812640	SCV002049433	uncertain significance	not provided	2021-04-29	criteria provided, single submitter	clinical testing	The MYH11 c.1574C>T; p.Pro525Leu variant (rs750288554), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 238257). This variant is found in the general population with an allele frequency of 0.0056% (14/251,054 alleles) in the Genome Aggregation Database. The proline at codon 525 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.705) and may impact splicing by weakening the nearby canonical donor splice site. Due to limited information, the clinical significance of the p.Pro525Leu variant is uncertain at this time.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150135	SCV003837940	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003150135	SCV003997501	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-22	criteria provided, single submitter	clinical testing	The p.P525L variant (also known as c.1574C>T), located in coding exon 12 of the MYH11 gene, results from a C to T substitution at nucleotide position 1574. The proline at codon 525 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV003150135	SCV004359447	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 532 of the MYH11 protein. Computational prediction suggests that this variant may have 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 MYH11-related disorders in the literature. This variant has been identified in 14/251054 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	RCV003150135	SCV004823653	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 532 of the MYH11 protein. This variant is also known as c.1574C>T, p.Pro525Leu based on transcript NM_002474.3. Computational prediction suggests that this variant may have 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 14/251054 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.