Submissions for variant NM_000138.5(FBN1):c.5279A>G (p.Tyr1760Cys)

dbSNP: rs1597543452

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801558	SCV000941338	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-05	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 647128). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1760 of the FBN1 protein (p.Tyr1760Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192952	SCV001361431	uncertain significance	not specified	2019-01-21	criteria provided, single submitter	clinical testing	Variant summary: The variant, FBN1 c.5279A>G (p.Tyr1760Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function although these predictions have yet to be functionally assessed. The variant was absent in 245332 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5279A>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, the FBN1 protein is composed of disulphide bonds and it has been well established that the sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. Therefore, the creation of a new cysteine site could lead to disruption of disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. Thus, the variant of interest is classified as VUS-possibly pathogenic until additional information becomes available.