Submissions for variant NM_001999.4(FBN2):c.3062G>C (p.Arg1021Pro)

dbSNP: rs139620380

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196006	SCV000250181	uncertain significance	not provided	2017-10-12	criteria provided, single submitter	clinical testing	p.Arg1021Pro (CGC>CCC): c.3062 G>C in exon 24 of the FBN2 gene (NM_001999.3) The R1021P variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge. The R1021P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1021P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is possibly damaging to protein structure/function. However, no missense mutations in nearby residues have been reported in association with congenital contractural arachnodactyly. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633600	SCV000754846	uncertain significance	Congenital contractural arachnodactyly	2022-02-04	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with FBN2-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 213298). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1021 of the FBN2 protein (p.Arg1021Pro).
Illumina Laboratory Services, Illumina	RCV000633600	SCV001315561	uncertain significance	Congenital contractural arachnodactyly	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.