ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.5921T>C (p.Ile1974Thr)

gnomAD frequency: 0.00004  dbSNP: rs765878996
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001183769 SCV000320460 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2015-11-14 criteria provided, single submitter clinical testing The p.I1974T variant (also known as c.5921T>C), located in coding exon 48 of the FBN1 gene, results from a T to C substitution at nucleotide position 5921. The isoleucine at codon 1974 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6494 samples (12988 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging but tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
CeGaT Center for Human Genetics Tuebingen RCV001093333 SCV001250260 uncertain significance not provided 2019-09-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001183769 SCV001349590 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-01-27 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 1974 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 cardiovascular disorders in the literature. This variant has been identified in 3/250880 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 RCV002487161 SCV002789653 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 2021-09-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002518732 SCV003256761 likely benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-10-22 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000663834 SCV004814618 uncertain significance Marfan syndrome 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 1974 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 cardiovascular disorders in the literature. This variant has been identified in 3/250880 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.
Center for Medical Genetics Ghent, University of Ghent RCV000663834 SCV000787191 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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