Submissions for variant NM_000138.5(FBN1):c.4012G>A (p.Val1338Ile)

gnomAD frequency: 0.00001  dbSNP: rs1416288007

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001053535	SCV001217802	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-10-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001797151	SCV002038649	uncertain significance	not provided	2021-06-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 849542; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; 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: 27535533, 26582918)
Color Diagnostics, LLC DBA Color Health	RCV003528263	SCV004357397	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1338 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 been reported in an individual clinical features of Marfan syndrome (ClinVar RCV001053535.6). This variant has been identified in 3/282644 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.
All of Us Research Program, National Institutes of Health	RCV004000063	SCV004814766	uncertain significance	Marfan syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1338 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 been reported in an individual clinical features of Marfan syndrome (ClinVar RCV001053535.6). This variant has been identified in 3/282644 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	RCV004768821	SCV005381446	uncertain significance	not specified	2024-08-28	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4012G>A (p.Val1338Ile) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251236 control chromosomes. 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.4012G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 849542). Based on the evidence outlined above, the variant was classified as uncertain significance.