Submissions for variant NM_000138.5(FBN1):c.4999G>A (p.Val1667Ile)

gnomAD frequency: 0.00002  dbSNP: rs140626

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466201	SCV000544908	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000163	SCV001156651	uncertain significance	not specified	2019-01-23	criteria provided, single submitter	clinical testing	The FBN1 c.4999G>A; p.Val1667Ile variant (rs140626) has been described in at least one individual affected with Marfan syndrome or a related connective tissue disorder (Liu 1997). It contains an entry in ClinVar (Variation ID: 406339) and is observed in the general population at a low overall frequency of 0.0035% (10/282608 alleles) in the Genome Aggregation Database. The valine at codon 1667 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. However, due to limited information regarding this variant, its clinical significance cannot be determined with certainty. REFERENCES Liu W et al. Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders. Genet Test. 1997;1(4):237-42.
Color Diagnostics, LLC DBA Color Health	RCV001185791	SCV001352086	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-07	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1667 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 10/282608 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.
Fulgent Genetics, Fulgent Genetics	RCV002481399	SCV002781795	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	2022-03-24	criteria provided, single submitter	clinical testing
GeneDx	RCV003235219	SCV003933455	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 11875032, 10464652, 11461921)
All of Us Research Program, National Institutes of Health	RCV004000736	SCV004814681	uncertain significance	Marfan syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1667 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 been reported in an individual affected with Marfan syndrome or a related connective tissue disorder (PMID: 10464652). This variant has been identified in 10/282608 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.