Submissions for variant NM_000138.5(FBN1):c.188A>G (p.Tyr63Cys)

dbSNP: rs1303389437

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000659499	SCV004218511	uncertain significance	Marfan syndrome	2023-12-21	reviewed by expert panel	curation	The NM_00138 c.188A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 63 (p.Tyr63Cys). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (PMID 17657824) (PP4). This variant in FBN1 has been reported three times in ClinVar: 1 time as uncertain significance, 1 time as likely pathogenic, and 1 time as pathogenic (Variation ID: 547296). This variant has previously been reported in at least two apparently unrelated individuals with ectopia lentis (PMID 25053872, 28941062) and in an individual with a suspected or confimed diagnosis of Marfan syndrome (Centre for Human Genetics, Inc. ClinVar entry) (PS4_mod). This variant has been identified in 1/112420 (0.0004%) individuals of European non-Finnish origin (https://gnomad.broadinstitute.org/version 2.1.1). Computational prediction tools and conservation analysis are inconclusive data with regards to a possible impact on this variant protein function and structure (REVEL: 0.72). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to the conflicting evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Mod, PP2, PP4
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659499	SCV000781318	likely pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001756116	SCV001986091	uncertain significance	not provided	2023-12-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); 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: 28941062, 25053872, 17657824, 20564469, 12938084)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855388	SCV002233030	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-12-21	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 547296). This missense change has been observed in individuals with FBN1-related conditions (PMID: 17657824, 25053872, 28941062). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the FBN1 protein (p.Tyr63Cys).