ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.5284G>A (p.Gly1762Ser)

dbSNP: rs387906623
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília RCV000022545 SCV000223903 pathogenic Geleophysic dysplasia 2 2015-04-01 criteria provided, single submitter research
GeneDx RCV000255619 SCV000321632 pathogenic not provided 2022-04-07 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); 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: 25525159, 25979247, 24339047, 21683322, 29191498, 27935852, 29620724, 31350823, 32005694, 33030311, 34006472, 33082559)
Eurofins Ntd Llc (ga) RCV000255619 SCV000344090 pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV004018662 SCV000742920 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-05-16 criteria provided, single submitter clinical testing The c.5284G>A (p.G1762S) alteration is located in exon 43 (coding exon 42) of the FBN1 gene. This alteration results from a G to A substitution at nucleotide position 5284, causing the glycine (G) at amino acid position 1762 to be replaced by a serine (S)._x000D_ _x000D_ Based on the available evidence, the FBN1 c.5284G>A (p.G1762S) alteration is classified as pathogenic for FBN1-related acromelic dysplasias; however, it is unlikely to be causative of either Marfan syndrome and related fibrillinopathies or Marfan lipodystrophy syndrome. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.5284G>A alteration has been previously reported as a recurrent de novo in multiple unrelated individuals with geleophysic dysplasia and acromelic dysplasia (Fan, 2021; Le Goff, 2011; Sun, 2020). Additionally, this alteration has been observed in heterozygous state in multiple other related and unrelated individuals with geleophysic and acromelic dysplasia (Cheng, 2018; Klein, 2014; Le Goff, 2011; Maddirevula, 2018; Marzin, 2021; Piccolo, 2019; Verberne, 2022). This amino acid position is highly conserved in available vertebrate species. Functional analysis by Jensen et al. (2015) demonstrated that the p.G1762S alteration resulted in normal or near normal protein secretion, consistent with other alterations associated with geleophysic dysplasia. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000255619 SCV001446985 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001389174 SCV001590442 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-09-10 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 29697). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with geleophysic dysplasia (PMID: 21683322, 27935852, 29620724). In at least one individual the variant was observed to be de novo. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1762 of the FBN1 protein (p.Gly1762Ser). This variant is not present in population databases (gnomAD no frequency).
Blueprint Genetics RCV000255619 SCV001832405 pathogenic not provided 2019-11-30 criteria provided, single submitter clinical testing
Pars Genome Lab RCV000022545 SCV001837609 pathogenic Geleophysic dysplasia 2 2021-09-08 criteria provided, single submitter clinical testing we found this variant in a 6-year-old girl with bone dysplasia.
Suma Genomics RCV000022545 SCV002605337 pathogenic Geleophysic dysplasia 2 criteria provided, single submitter clinical testing
OMIM RCV000022545 SCV000043834 pathogenic Geleophysic dysplasia 2 2018-01-04 no assertion criteria provided literature only

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