Submissions for variant NM_000138.5(FBN1):c.2434G>A (p.Glu812Lys)

gnomAD frequency: 0.00006  dbSNP: rs201778577

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181461	SCV000233763	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; 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).; This variant is associated with the following publications: (PMID: 12938084)
Color Diagnostics, LLC DBA Color Health	RCV000778031	SCV000914143	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 812 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 11/282390 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000181461	SCV001159756	uncertain significance	not provided	2023-10-04	criteria provided, single submitter	clinical testing	The FBN1 c.2434G>A; p.Glu812Lys variant (rs201778577), to our knowledge, is not described in the medical literature but is reported as a variant of uncertain significance in ClinVar (Variation ID: 199997). It is observed in the general population at an overall frequency of 0.004% (11/282390 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.302). While present in the EGF domain, this variant does not disrupt the EGF consensus motif, and therefore does not meet the automatic threshold for Ghent criteria. Due to limited information, the clinical significance of this variant is uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852278	SCV002198506	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002503704	SCV002815186	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	2021-09-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993865	SCV004813278	uncertain significance	not specified	2024-02-05	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.2434G>A (p.Glu812Lys) results in a conservative amino acid change located in the EGF like domain (IPR000742) of 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 3.9e-05 in 1613876 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FBN1 causing Aortopathy (3.9e-05 vs 0.00011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2434G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 199997). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000663541	SCV004814901	uncertain significance	Marfan syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 812 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 11/282390 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.
Center for Medical Genetics Ghent, University of Ghent	RCV000663541	SCV000786852	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing