Submissions for variant NM_000138.5(FBN1):c.1856C>A (p.Thr619Asn)

gnomAD frequency: 0.00001  dbSNP: rs377686210

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699001	SCV000827693	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182973	SCV001348612	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 619 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 12/251422 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001182973	SCV002041955	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-07-13	criteria provided, single submitter	clinical testing
GeneDx	RCV002286782	SCV002576970	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; 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)
Fulgent Genetics, Fulgent Genetics	RCV002485711	SCV002780995	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	2021-10-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999686	SCV004823026	uncertain significance	Marfan syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 619 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 12/251422 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	RCV001182973	SCV005113161	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-05-17	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.