Submissions for variant NM_000138.5(FBN1):c.3226A>C (p.Ile1076Leu)

gnomAD frequency: 0.00008  dbSNP: rs201156527

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465841	SCV000544951	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-08-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000520471	SCV000616716	uncertain significance	not provided	2020-06-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV001187622	SCV001354473	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 1076 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 8/282874 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.
Fulgent Genetics, Fulgent Genetics	RCV002480367	SCV002792137	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	2021-10-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000737	SCV004814822	uncertain significance	Marfan syndrome	2023-09-04	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 1076 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 8/282874 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.
Ambry Genetics	RCV001187622	SCV005113157	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-03-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.