Submissions for variant NM_000138.5(FBN1):c.139G>A (p.Gly47Ser)

gnomAD frequency: 0.00003  dbSNP: rs762400500

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726149	SCV000233804	uncertain significance	not provided	2024-07-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign in association with FBN1-related disorders to our knowledge; 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; Does not affect a cysteine or calcium-binding residue within an EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 28054583, 12938084)
Eurofins Ntd Llc (ga)	RCV000726149	SCV000342417	uncertain significance	not provided	2016-07-07	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414982	SCV000492707	uncertain significance	Dental crowding; Arachnodactyly; Dolichocephaly; Joint hypermobility; Aortic regurgitation; High, narrow palate	2015-10-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533830	SCV000627835	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-11	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170559	SCV001333145	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170559	SCV001347033	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 47 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 5/282778 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.
CeGaT Center for Human Genetics Tuebingen	RCV000726149	SCV004129824	likely benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing	FBN1: PP2, BS2
All of Us Research Program, National Institutes of Health	RCV003996685	SCV004823153	uncertain significance	Marfan syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 47 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 5/282778 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.
Ambry Genetics	RCV001170559	SCV005113190	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-06-06	criteria provided, single submitter	clinical testing	The p.G47S variant (also known as c.139G>A), located in coding exon 1 of the FBN1 gene, results from a G to A substitution at nucleotide position 139. The glycine at codon 47 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.