Submissions for variant NM_000138.5(FBN1):c.5183C>T (p.Ala1728Val)

dbSNP: rs1131691804

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493791	SCV000582880	pathogenic	not provided	2020-07-06	criteria provided, single submitter	clinical testing	Not observed 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: 21683322, 27245183)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626616	SCV000747317	pathogenic	Metaphyseal chondrodysplasia	2017-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626617	SCV000747318	likely pathogenic	Short stature; Wide mouth; Wide nasal bridge; Relative macrocephaly	2017-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779168	SCV000915687	likely pathogenic	Geleophysic dysplasia	2017-04-27	criteria provided, single submitter	clinical testing	The FBN1 c.5183C>T (p.Ala1728Val) missense variant has been reported in two studies and found in a total of four individuals from three unrelated families affected with FBN1-related disorders, including acromicric dysplasia and geleophysic dysplasia, all in a heterozygous state (Le Goff et al. 2011; de Bruin et al. 2016). The individual reported in Le Goff et al. (2011) study was de novo for the variant, while one patient reported in de Bruin et al. (2016) study inherited the variant from affected mother. The variant was absent from the 1000 Genomes Project, Exome Sequencing Project, the Exome Aggregation Consortium and the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence, the p.Ala1728Val is classified as likely pathogenic for FBN1-related disorders. This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001387308	SCV001587905	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1728 of the FBN1 protein (p.Ala1728Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of acromicric dysplasia or geleophysic dysplasia (PMID: 21683322, 27245183). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430150). 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. This variant disrupts the p.Ala1728 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21683322). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279270	SCV002566535	likely pathogenic	Connective tissue disorder	2022-06-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000493791	SCV003917382	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	FBN1: PM2, PM6, PS4:Moderate, PP1, PP2, PP3, PP4
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV001293674	SCV001482391	likely pathogenic	Geleophysic dysplasia 2	2019-05-31	no assertion criteria provided	research
Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital	RCV004556061	SCV005045298	likely pathogenic	Acromicric dysplasia	2024-02-01	no assertion criteria provided	clinical testing