Submissions for variant NM_000138.5(FBN1):c.6161A>G (p.Gln2054Arg)

dbSNP: rs2043116342

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001208198	SCV001379574	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-11-12	criteria provided, single submitter	clinical testing	This variant disrupts the p.Gln2054 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 11139245), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 938898). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 2054 of the FBN1 protein (p.Gln2054Arg). 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.
Fulgent Genetics, Fulgent Genetics	RCV002480681	SCV002786810	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	2021-10-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004010666	SCV004829693	uncertain significance	Marfan syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 2054 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 one individual affected with sudden infant death (PMID: 30086531). This variant has not been identified 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	RCV004768918	SCV005377776	uncertain significance	not provided	2023-12-13	criteria provided, single submitter	clinical testing	Reported in an infant with sudden unexplained death (PMID: 30086531); 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 (PMID: 12938084); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36693943, 12938084, 30086531)
PreventionGenetics, part of Exact Sciences	RCV004738190	SCV005354818	uncertain significance	FBN1-related disorder	2024-08-22	no assertion criteria provided	clinical testing	The FBN1 c.6161A>G variant is predicted to result in the amino acid substitution p.Gln2054Arg. This variant has been observed in an individual from a cohort of infants with sudden unexplained death (SIDS) (Campuzano et al. 2018. PubMed ID: 30086531; variant reevaluated in Martinez-Barrios et al. 2023. PubMed ID: 36693943) and reported as variant of uncertain significance. This variant has not been reported in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.