Submissions for variant NM_000138.5(FBN1):c.8300A>G (p.Asn2767Ser)

gnomAD frequency: 0.00006  dbSNP: rs536503540

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471343	SCV000544880	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155187	SCV000695621	uncertain significance	not specified	2024-06-04	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.8300A>G (p.Asn2767Ser) results in a 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 6.8e-05 in 251352 control chromosomes, predominantly at a frequency of 0.00042 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011). c.8300A>G has been reported in the literature in individuals affected with Marfan syndrome and idiopathic scoliosis without evidence of cosegregation (Haller_2015, Groth_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. The following publications have been ascertained in the context of this evaluation (PMID: 26333736, 27906200, 30653986). ClinVar contains an entry for this variant (Variation ID: 406312). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV001177373	SCV001341571	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-16	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 2767 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 an individual affected with adolescent idiopathic scoliosis (PMID: 26333736). This variant has been identified in 19/282752 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.
CeGaT Center for Human Genetics Tuebingen	RCV000587559	SCV001370970	uncertain significance	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001177373	SCV002681938	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-02-04	criteria provided, single submitter	clinical testing	The p.N2767S variant (also known as c.8300A>G), located in coding exon 65 of the FBN1 gene, results from an A to G substitution at nucleotide position 8300. The asparagine at codon 2767 is replaced by serine, an amino acid with highly similar properties. This variant has been detected in an individual with idiopathic scoliosis and in an individual with non-syndromic pediatric glaucoma (Haller G et al. J Bone Joint Surg Am, 2015 Sep;97:1411-7; Patel A et al. Ophthalmology, 2019 06;126:888-907). This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002481398	SCV002782696	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	2021-11-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001177373	SCV003838335	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-03-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000734	SCV004844901	uncertain significance	Marfan syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 2767 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 an individual affected with adolescent idiopathic scoliosis (PMID: 26333736). This variant has been identified in 19/282752 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000587559	SCV002035469	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587559	SCV002038196	likely benign	not provided		no assertion criteria provided	clinical testing