Submissions for variant NM_000090.4(COL3A1):c.4075C>A (p.Leu1359Ile)

gnomAD frequency: 0.00004  dbSNP: rs1400489265

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000559500	SCV000631669	uncertain significance	Ehlers-Danlos syndrome, type 4	2017-05-15	criteria provided, single submitter	clinical testing	In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL3A1-related disease. This sequence change replaces leucine with isoleucine at codon 1359 of the COL3A1 protein (p.Leu1359Ile). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and isoleucine.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003485600	SCV004240474	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000559500	SCV005427406	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 1359 of the COL3A1 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 COL3A1-related disorders in the literature. This variant has not been identified 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.