Submissions for variant NM_000138.5(FBN1):c.4336+4A>C

gnomAD frequency: 0.00002  dbSNP: rs764099050

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002314344	SCV000738860	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-01-03	criteria provided, single submitter	clinical testing	The c.4336+4A>C intronic variant results from an A to C substitution 4 nucleotides after coding exon 34 in the FBN1 gene. This nucleotide position is well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to weaken the efficiency of the native splice donor site, but is not predicted to have a deleterious effect on this splice donor site by BDGP; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175568	SCV001339195	uncertain significance	not specified	2020-03-02	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4336+4A>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 251112 control chromosomes (gnomAD). 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.4336+4A>C in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868122	SCV002211089	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-02-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 35 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs764099050, gnomAD 0.007%). 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: 519751). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Color Diagnostics, LLC DBA Color Health	RCV002314344	SCV004357384	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-25	criteria provided, single submitter	clinical testing	This variant causes an A to C nucleotide substitution at the +4 position of intron 35 of the FBN1 gene. 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 7/251112 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.
PreventionGenetics, part of Exact Sciences	RCV004544810	SCV004788144	likely benign	FBN1-related disorder	2019-04-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).