Submissions for variant NM_000138.5(FBN1):c.8039G>A (p.Arg2680His)

gnomAD frequency: 0.00001  dbSNP: rs748934203

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631922	SCV000753025	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-07-13	criteria provided, single submitter	clinical testing	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. 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: 527153). This missense change has been observed in individuals with clinical features of FBN1-related conditions (Invitae). This variant is present in population databases (rs748934203, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2680 of the FBN1 protein (p.Arg2680His).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170298	SCV001332862	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-02-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702216	SCV005205320	uncertain significance	not specified	2024-06-26	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.8039G>A (p.Arg2680His) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249436 control chromosomes. 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.8039G>A in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 527153). Based on the evidence outlined above, the variant was classified as uncertain significance.