ClinVar Miner

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

dbSNP: rs1303389437
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Total submissions: 4
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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 2020-09-11 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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)
Invitae RCV001855388 SCV002233030 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2021-12-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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. 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).

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