Submissions for variant NM_000138.5(FBN1):c.5674A>G (p.Ile1892Val)

dbSNP: rs760170973

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170537	SCV001333122	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-02-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170537	SCV002051905	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1892 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 FBN1-related disorders in the literature. This variant has been identified in 6/250910 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331059	SCV004039472	uncertain significance	not specified	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.5674A>G (p.Ile1892Val) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. In addition, this variant disrupts the third nucleotide of exon 47, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 250910 control chromosomes (i.e., 6 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5674A>G in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003769838	SCV004578085	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1892 of the FBN1 protein (p.Ile1892Val). This variant is present in population databases (rs760170973, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 915613). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV004000273	SCV004814640	uncertain significance	Marfan syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1892 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 6/250910 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.