Submissions for variant NM_000138.5(FBN1):c.8232G>C (p.Gln2744His)

dbSNP: rs376119827

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546431	SCV000628007	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765217	SCV000896453	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	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181857	SCV001347099	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 2744 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysm and aortic dissection and/or bicuspid aortic valve (PMID: 28659821, 29907982). This variant has been identified in 3/250796 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.
GeneDx	RCV001591196	SCV001826981	uncertain significance	not provided	2020-07-27	criteria provided, single submitter	clinical testing	Reported in a proband with a history of a carotid artery dissection, borderline aortic root aneurysm, and pneumothorax (Overwater et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter 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); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 457269; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29907982)
Johns Hopkins Genomics, Johns Hopkins University	RCV002282205	SCV002570271	uncertain significance	Marfan syndrome	2022-04-29	criteria provided, single submitter	clinical testing	FBN1 c.8232G>C has been identified in a single individual with features of an FBN1-related condition. This FBN1 variant(rs376119827) is rare (<0.1%) in a large population dataset (gnomAD: 3/250796 total alleles; 0.001196%; no homozygotes) and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be tolerated and the glutamine residue at this position is not highly evolutionarily conserved across the species assessed. We consider the clinical significance of FBN1 c.8232G>C to be uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298645	SCV002598555	uncertain significance	not specified	2022-09-12	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.8232G>C (p.Gln2744His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250796 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8232G>C has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual affected with suspected heritable thoracic aortic disorders (example, Overwater_2018) and also in an individual undergoing candidate gene resequencing In a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort (example, Gillis_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV001181857	SCV002676139	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-03-20	criteria provided, single submitter	clinical testing	The p.Q2744H variant (also known as c.8232G>C), located in coding exon 65 of the FBN1 gene, results from a G to C substitution at nucleotide position 8232. The glutamine at codon 2744 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in a subject with carotid artery dissection, aortic aneurysm and pneumothorax (Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV002282205	SCV004844906	uncertain significance	Marfan syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 2744 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysm and aortic dissection and/or bicuspid aortic valve (PMID: 28659821, 29907982). This variant has been identified in 3/250796 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001591196	SCV001929908	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001591196	SCV001975192	likely benign	not provided		no assertion criteria provided	clinical testing