Submissions for variant NM_000089.4(COL1A2):c.3226C>T (p.Pro1076Ser)

dbSNP: rs763974489

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001249740	SCV001423772	uncertain significance	Ehlers-Danlos syndrome, arthrochalasis type	2020-03-26	criteria provided, single submitter	clinical testing	The COL1A2 c.3226C>T (p.Pro1076Ser) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. The variant has not been reported in association with Ehlers-Danlos syndrome, though it has been reported in a heterozygous state in one individual with incontinentia pigmenti and cleft palate who also carried variants in several other genes, at least one of which was thought to be causative for the phenotype (Pengelly et al. 2015). This variant is reported at a frequency of 0.000058 in the Latino population from the Genome Aggregation Database, though this is based on two alleles in a region of good sequencing coverage so the variant is presumed to be rare. Based on the limited evidence, the p.Pro1076Ser variant is classified as a variant of unknown significance for the arthrochalasia type of Ehlers-Danlos syndrome.
Invitae	RCV001879761	SCV002140336	uncertain significance	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1076 of the COL1A2 protein (p.Pro1076Ser). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with COL1A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 973298). 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 COL1A2 protein function with a negative predictive value of 95%. 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.
GeneDx	RCV003332315	SCV004039722	uncertain significance	not provided	2023-09-29	criteria provided, single submitter	clinical testing	Observed in an individual in published literature (Pengelly et al., 2015) who had additional genetic variants likely to explain the phenotype.; Not observed at significant frequency in large population cohorts (gnomAD); Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25441681)