Submissions for variant NM_000138.5(FBN1):c.4150A>G (p.Met1384Val)

gnomAD frequency: 0.00006  dbSNP: rs775543440

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704866	SCV000233813	uncertain significance	not provided	2024-05-15	criteria provided, single submitter	clinical testing	Identified in a patient with sudden unexplained death in the published literature (PMID: 26272908); In silico analysis indicates 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 (PMID: 12938084); This variant is associated with the following publications: (PMID: 26272908, 12938084)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170774	SCV001333380	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-07-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170774	SCV001340892	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1384 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 sudden unexpected death in infancy and early childhood (PMID: 26272908). This variant has been identified in 9/282718 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001341819	SCV001535711	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001170774	SCV002629021	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-10-19	criteria provided, single submitter	clinical testing	The p.M1384V variant (also known as c.4150A>G), located in coding exon 33 of the FBN1 gene, results from an A to G substitution at nucleotide position 4150. The methionine at codon 1384 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in a sudden unexplained death in infancy cohort; however, clinical details were limited (Santori M et al. Arch Dis Child, 2015 Oct;100:952-6). This amino acid position is not 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.
Fulgent Genetics, Fulgent Genetics	RCV002485194	SCV002794011	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	2021-08-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996686	SCV004814759	uncertain significance	Marfan syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1384 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 sudden unexpected death in infancy and early childhood (PMID: 26272908). This variant has been identified in 9/282718 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.