Submissions for variant NM_000138.5(FBN1):c.4437C>G (p.Asp1479Glu)

dbSNP: rs370161725

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181520	SCV000233823	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	Reported in the Universal Mutation Database (UMD) in a female proband with joint hypermobility, arachnodactyly, and dolichocephaly (Beroud et al., 2000; James Hyland, personal communication, 2003); Identified in several individuals referred for connective tissue disorder genetic testing at GeneDx, but segregation data are inconclusive thus far; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24833718, 27906200, 10612827, 12938084)
Invitae	RCV000465923	SCV000544865	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1479 of the FBN1 protein (p.Asp1479Glu). This variant is present in population databases (rs370161725, gnomAD 0.002%). This missense change has been observed in individuals with FBN1-related conditions (PMID: 27906200; Invitae). ClinVar contains an entry for this variant (Variation ID: 200044). 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%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000181520	SCV000927534	uncertain significance	not provided	2018-02-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001178817	SCV001343351	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 1479 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Marfan syndrome (PMID: 12938084). This variant has also been identified in 3/251272 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	RCV001192802	SCV001361162	uncertain significance	not specified	2019-05-26	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4437C>G (p.Asp1479Glu) results in a conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. This missense change does not involve a Cysteine residue. Cysteine residues are involved in disulfide bonding; introduction or substitution of these residues within the calcium-binding EGF-like domains represent the majority of pathogenic missense changes occuring in Marfan syndrome (Collod-Beroud_2003). 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 1.2e-05 in 251272 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4437C>G has been reported in individual(s) affected with Marfan syndrome (Groth_2016, UMD database). However, these reports do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002500530	SCV002813483	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	2021-11-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996687	SCV004814727	uncertain significance	Marfan syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 1479 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Marfan syndrome (PMID: 12938084). This variant has also been identified in 3/251272 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.