Submissions for variant NM_000138.5(FBN1):c.1970T>C (p.Met657Thr)

dbSNP: rs2043686451

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001179939	SCV001344742	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 657 of the FBN1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV002265005	SCV002546761	uncertain significance	not provided	2022-06-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003769953	SCV004578143	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 657 of the FBN1 protein (p.Met657Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 920886). 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. 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.
All of Us Research Program, National Institutes of Health	RCV004006614	SCV004823021	uncertain significance	Marfan syndrome	2023-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 657 of the FBN1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.