Submissions for variant NM_000138.5(FBN1):c.2926C>T (p.Arg976Cys)

gnomAD frequency: 0.00001  dbSNP: rs548296552

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181470	SCV000233772	likely pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	Introduces a new cysteine residue within a TGF-binding protein domain (aka TB domain or 8-Cysteine domain) and is expected to disrupt disulfide bonding within this domain; other missense substitutions that affect cysteine residues within this TGF-binding protein domain have been reported in association with various FBN1-related phenotypes, including Marfan syndrome (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with TAAD in the published literature (Li et al., 2021); This variant is associated with the following publications: (PMID: 31589614, 33824467)
Invitae	RCV001057247	SCV001221730	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-12	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with FBN1-related conditions (PMID: 33824467). This variant is present in population databases (rs548296552, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 976 of the FBN1 protein (p.Arg976Cys). ClinVar contains an entry for this variant (Variation ID: 200006). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192951	SCV001361430	uncertain significance	not specified	2019-03-04	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.2926C>T (p.Arg976Cys) results in a non-conservative amino acid change located in the TB domain (IPR017878) 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 1.4e-05 in 277204 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.2926C>T in individuals affected with Marfan Syndrome 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. Missense affecting or creating cysteine residues are listed as one of the criteria for causal FBN1 mutations in the revised Ghent criteria for the diagnosis of Marfan syndrome (MFS) and related conditions (Loeys BL et al., J Med Genet 2010; 47:476-485). Based on the evidence outlined above, unless additional clinical and functional evidence are obtained, the variant was classified as VUS-possibly pathogenic.
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374768	SCV001439549	uncertain significance	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
AiLife Diagnostics, AiLife Diagnostics	RCV000181470	SCV002503052	uncertain significance	not provided	2021-11-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996679	SCV004814855	uncertain significance	Marfan syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 976 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with thoracic aortic aneurysm (PMID: 33824467). This variant has also been reported in multiple other individuals but whether they are affected with FBN1-related disorders is not clear in the publications (PMID: 31589614, 32989268). This variant has been identified in 4/282846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.