Submissions for variant NM_000138.5(FBN1):c.124G>C (p.Ala42Pro)

gnomAD frequency: 0.00006  dbSNP: rs377722423

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458251	SCV000544884	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000729437	SCV000857102	uncertain significance	not provided	2017-10-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170560	SCV001333146	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170560	SCV001346804	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 42 of the FBN1 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 FBN1-related disorders in the literature. This variant has been identified in 15/282810 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194180	SCV001363514	uncertain significance	not specified	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.124G>C (p.Ala42Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251464 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FBN1 causing Marfan Syndrome (4.4e-05 vs 0.00011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.124G>C in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=5, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000729437	SCV001774227	uncertain significance	not provided	2024-08-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27906200)
Ambry Genetics	RCV001170560	SCV002672170	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-03	criteria provided, single submitter	clinical testing	The p.A42P variant (also known as c.124G>C), located in coding exon 1 of the FBN1 gene, results from a G to C substitution at nucleotide position 124. The alanine at codon 42 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in a database of subjects with features of Marfan syndrome (Groth KA et al. Genet Med, 2017 Jul;19:772-777). This amino acid position is highly conserved in available vertebrate species. 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.
All of Us Research Program, National Institutes of Health	RCV004000735	SCV004823157	uncertain significance	Marfan syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 42 of the FBN1 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 15/282810 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.