Submissions for variant NM_000089.4(COL1A2):c.1148C>A (p.Pro383His)

gnomAD frequency: 0.00004  dbSNP: rs193922159

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824577	SCV000052241	likely benign	not specified	2022-01-29	criteria provided, single submitter	clinical testing	Variant summary: COL1A2 c.1148C>A (p.Pro383His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 188644 control chromosomes. The observed variant frequency is approximately 1.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A2 causing Osteogenesis Imperfecta phenotype (2.8e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1148C>A in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant(s) have been observed at our laboratory (COL1A1 c.3421C>T, p.Arg1141Ter), providing supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV002228061	SCV000955222	uncertain significance	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-08-18	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. This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 383 of the COL1A2 protein (p.Pro383His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 35933). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL1A2 protein function.
GeneDx	RCV001770043	SCV002002749	uncertain significance	not provided	2022-04-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have aneffect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31589614)
Ambry Genetics	RCV002453270	SCV002615248	uncertain significance	Cardiovascular phenotype	2022-02-22	criteria provided, single submitter	clinical testing	The p.P383H variant (also known as c.1148C>A), located in coding exon 21 of the COL1A2 gene, results from a C to A substitution at nucleotide position 1148. The proline at codon 383 is replaced by histidine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.