Submissions for variant NM_000138.5(FBN1):c.8179G>A (p.Gly2727Ser)

gnomAD frequency: 0.00004  dbSNP: rs758748297

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000592580	SCV000703174	uncertain significance	not provided	2016-11-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001189489	SCV000738871	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-02-08	criteria provided, single submitter	clinical testing	The p.G2727S variant (also known as c.8179G>A), located in coding exon 64 of the FBN1 gene, results from a G to A substitution at nucleotide position 8179. The glycine at codon 2727 is replaced by serine, an amino acid with similar properties, and is located in the fibulin-like C-terminal domain. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001189489	SCV001356796	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 2727 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 6/282864 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001189489	SCV002042020	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-01-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001867932	SCV002188347	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2727 of the FBN1 protein (p.Gly2727Ser). This variant is present in population databases (rs758748297, gnomAD 0.004%). 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: 498253). 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"). 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.
GeneDx	RCV000592580	SCV002574647	uncertain significance	not provided	2022-09-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein 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)
Fulgent Genetics, Fulgent Genetics	RCV002476288	SCV002789708	uncertain significance	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-10-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488713	SCV004241698	uncertain significance	not specified	2023-12-27	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.8179G>A (p.Gly2727Ser) 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. The variant allele was found at a frequency of 2e-05 in 251464 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.8179G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004002456	SCV004844919	uncertain significance	Marfan syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 2727 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/282864 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.