Submissions for variant NM_000090.4(COL3A1):c.2264C>A (p.Pro755Gln)

gnomAD frequency: 0.00001  dbSNP: rs1553508711

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000634722	SCV000756060	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-01-19	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 protein function. ClinVar contains an entry for this variant (Variation ID: 529325). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 755 of the COL3A1 protein (p.Pro755Gln).
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002286767	SCV002577568	likely pathogenic	Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2022-03-28	criteria provided, single submitter	clinical testing	PM1, PM2, PP2, PP3
All of Us Research Program, National Institutes of Health	RCV000634722	SCV004825420	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces proline with glutamine at codon 755 of the COL3A1 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 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.