Submissions for variant NM_000138.5(FBN1):c.6623A>G (p.Asn2208Ser)

gnomAD frequency: 0.00003  dbSNP: rs146063839

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000797740	SCV000937319	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2208 of the FBN1 protein (p.Asn2208Ser). This variant is present in population databases (rs146063839, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of FBN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 643925). 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 expected to disrupt FBN1 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170528	SCV001333111	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-12-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170528	SCV001341191	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 2208 of the FBN1 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 FBN1-related disorders in the literature. This variant has been identified in 8/282250 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	RCV001194209	SCV001363559	uncertain significance	not specified	2020-10-06	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.6623A>G (p.Asn2208Ser) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250856 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6623A>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001553123	SCV001773936	uncertain significance	not provided	2022-09-12	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; 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: 20591885, 26582918)
Ambry Genetics	RCV001170528	SCV002663173	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-26	criteria provided, single submitter	clinical testing	The p.N2208S variant (also known as c.6623A>G), located in coding exon 54 of the FBN1 gene, results from an A to G substitution at nucleotide position 6623. The asparagine at codon 2208 is replaced by serine, an amino acid with highly similar properties. 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.
Fulgent Genetics, Fulgent Genetics	RCV002487671	SCV002781362	uncertain significance	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2022-02-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001553123	SCV003833991	uncertain significance	not provided	2020-08-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001612	SCV004822437	uncertain significance	Marfan syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 2208 of the FBN1 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 cardiovascular disorders in the literature. This variant has been identified in 8/282250 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.