Submissions for variant NM_000089.4(COL1A2):c.2569C>T (p.Pro857Ser)

dbSNP: rs150179964

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000354454	SCV000470613	uncertain significance	Ehlers-danlos syndrome, arthrochalasia type, 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000259604	SCV000470614	uncertain significance	Osteogenesis imperfecta	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001568227	SCV001792062	uncertain significance	not provided	2022-12-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; 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 an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD)
Ambry Genetics	RCV002429327	SCV002740272	uncertain significance	Cardiovascular phenotype	2019-11-14	criteria provided, single submitter	clinical testing	The p.P857S variant (also known as c.2569C>T), located in coding exon 41 of the COL1A2 gene, results from a C to T substitution at nucleotide position 2569. The proline at codon 857 is replaced by serine, an amino acid with similar properties. An alternate amino acid substitution at this position, p.P857T (c.2569C>A), has been reported in individuals with osteogenesis imperfecta; however, affected individuals also had additional collagen-related variants detected (Ho Duy B et al. Hum. Genomics, 2016 08;10:27; Li L et al. Hum. Mutat., 2019 05;40:588-600; Wang D et al. Front Endocrinol (Lausanne), 2019 Mar;10:193). This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other 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.
Invitae	RCV002524536	SCV003005586	uncertain significance	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2022-05-27	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 857 of the COL1A2 protein (p.Pro857Ser). This variant is present in population databases (rs150179964, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with COL1A2-related conditions. 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 COL1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 360965).