Submissions for variant NM_000138.5(FBN1):c.4313G>A (p.Ser1438Asn)

gnomAD frequency: 0.00001  dbSNP: rs587782945

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181517	SCV000233820	uncertain significance	not provided	2014-03-15	criteria provided, single submitter	clinical testing	p.Ser1438Asn (AGT>AAT): c.4313 G>A (NM_000138.4) The S1438N variant has not been published as a mutation or as a benign polymorphism to our knowledge. No population data is available for this substitution. The S1438N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species within the calcium binding domain. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in nearby residues (C1431W, C1431Y, C1429S, Y1427C, Y1427D) have been reported in association with Marfan syndrome, supporting the functional importance of this region of the protein, however most of them involve a Cysteine substitution.Therefore, based on the currently available information, it is unclear whether these variants are pathogenic mutations or a rare benign variants. The variant is found in TAAD panel(s).
Illumina Laboratory Services, Illumina	RCV000381005	SCV000392354	uncertain significance	Geleophysic dysplasia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000291329	SCV000392355	uncertain significance	Acromicric dysplasia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000346355	SCV000392356	uncertain significance	Ectopia lentis	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000405079	SCV000392357	uncertain significance	Stiff skin syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000302074	SCV000392358	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000143892	SCV000392359	uncertain significance	Marfan syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000397810	SCV000392360	uncertain significance	MASS syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000298555	SCV000392361	uncertain significance	Weill-Marchesani syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818523	SCV000959142	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-06-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000302074	SCV001343972	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1438 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 7/282724 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	RCV000302074	SCV002626799	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-11-16	criteria provided, single submitter	clinical testing	The p.S1438N variant (also known as c.4313G>A), located in coding exon 34 of the FBN1 gene, results from a G to A substitution at nucleotide position 4313. The serine at codon 1438 is replaced by asparagine, an amino acid with highly similar properties, and is located in the cbEGF-like #20 domain. This amino acid position is not well 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	RCV000143892	SCV004814740	uncertain significance	Marfan syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1438 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 7/282724 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.
Blueprint Genetics	RCV000143892	SCV000188761	uncertain significance	Marfan syndrome	2014-01-29	no assertion criteria provided	clinical testing