Submissions for variant NM_000138.5(FBN1):c.3963A>G (p.Thr1321=)

dbSNP: rs140648

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000621176	SCV000739790	likely pathogenic	Cardiovascular phenotype	2015-09-17	criteria provided, single submitter	clinical testing	The c.3963A>G variant (also known as p.T1321T), located in coding exon 31, results from an A to G substitution at nucleotide position 3963 of the FBN1 gene. This nucleotide substitution does not change the amino acid at codon 1321. In one study, this substitution was found to alter the second to last nucleotide of codingexon31 and resulted inexonskipping and abnormal splicing detected byRT-PCRanalysis of total RNA isolated from cultured fibroblasts (Liu et al.Genet Test. 1997-1998;1(4):237-242).In another study, this variant was reported in a patient with predominantectopialentisand other features ofMarfansyndrome (ComeglioP et al.Br JOphthalmol. 2002: 86(12); 1359-1362).This sequence variation was also reported in a patient and his similarly affected daughter, though the authors suggested the possibility that an additional mutation may exist that was not detected byheteroduplexanalysis (HallidayD et al.Hum Genet. 1999; 105(6): 587-597). It was also detected inan individual presented with skeletal system involved, aortic dilatation and family history ofectopia lentis but did not fulfillGhentcriteria (Turner CL et al, Am. J. Med. Genet. A 2009 Feb;149A(2):161-70).This variant was previously reported in the SNPDatabase as rs140648. It<span style="font-family:arial,sans-serif; font-size:10pt">was not reported in population based cohorts in the following databases: NHLBIExomeSequencing Project (ESP)and 1000 Genomes Project. In the ESP, this variant was not observed in 6494<span style="font-family:arial,sans-serif; font-size:10pt">samples (12988 alleles) with coverage at this position.<span style="line-height:13.8667px">Using theBDGP<span style="line-height:13.8667px">andESEfinder<span style="line-height:13.8667px">splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable.<span style="font-family:arial,sans-serif; font-size:10pt">Another algorithm also predicted the variant to cause aberrant splicing (Sahashi<span style="line-height:1.6">K et al<span style="line-height:1.6">, <em style="line-height:1.6">Nucleic Acids Res<span style="line-height:1.6">. 2007<span style="line-height:1.6">; 35(18):5995-6003).Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Centre of Medical Genetics, University of Antwerp	RCV000663678	SCV002025291	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531859	SCV003442940	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change affects codon 1321 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of FBN1-related conditions (PMID: 10464652, 10647894, 12446365, 17657824, 19161152, 35058154). ClinVar contains an entry for this variant (Variation ID: 520237). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000663678	SCV000787009	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing