Submissions for variant NM_000138.5(FBN1):c.4163G>A (p.Arg1388His)

gnomAD frequency: 0.00004  dbSNP: rs749196340

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659540	SCV000781367	uncertain significance	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817718	SCV000958296	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001180615	SCV001345581	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1388 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 6/282700 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.
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374761	SCV001439542	uncertain significance	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
GeneDx	RCV002285393	SCV002576072	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing	Identified in a patient with sudden unexplained death (SUD) and in a cohort of individuals with isolated TAAD in published literature (Sanchez et al., 2016; Li et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on 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: 33824467, 27930701, 12938084)
Fulgent Genetics, Fulgent Genetics	RCV002485503	SCV002789209	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	2021-11-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001180615	SCV003998983	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-14	criteria provided, single submitter	clinical testing	The p.R1388H variant (also known as c.4163G>A), located in coding exon 33 of the FBN1 gene, results from a G to A substitution at nucleotide position 4163. The arginine at codon 1388 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a sudden unexplained death cohort and a thoracic aortic aneurysm and dissection cohort; however, clinical details were limited in both cases (Sanchez O et al. PLoS One, 2016 Dec;11:e0167358; Li Y et al. Eur J Hum Genet, 2021 Jul;29:1129-1138). This amino acid position is well 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.
CeGaT Center for Human Genetics Tuebingen	RCV002285393	SCV004033382	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000659540	SCV004814756	uncertain significance	Marfan syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1388 of the FBN1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/282700 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.