Submissions for variant NM_000089.4(COL1A2):c.2425C>T (p.Pro809Ser)

gnomAD frequency: 0.00032  dbSNP: rs145355907

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497839	SCV000589466	uncertain significance	not provided	2017-12-21	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the COL1A2 gene. The P809S variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 27/66740 (0.04%) alleles from individuals of European ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). The P809S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae	RCV002231166	SCV000627314	likely benign	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2024-01-20	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680488	SCV000807866	uncertain significance	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000791269	SCV000930555	uncertain significance	Predisposition to dissection	2019-03-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000497839	SCV001155149	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	COL1A2: PM1
Illumina Laboratory Services, Illumina	RCV001164726	SCV001326875	benign	Ehlers-danlos syndrome, arthrochalasia type, 2	2018-01-12	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001164727	SCV001326876	likely benign	Osteogenesis imperfecta	2018-01-12	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001164727	SCV002564787	uncertain significance	Osteogenesis imperfecta	2019-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002446967	SCV002732891	likely benign	Cardiovascular phenotype	2023-02-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114623	SCV003800622	likely benign	not specified	2023-01-12	criteria provided, single submitter	clinical testing	Variant summary: COL1A2 c.2425C>T (p.Pro809Ser) 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 0.00021 in 251462 control chromosomes (gnomAD), predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2425C>T in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. Nine ClinVar submitters have assessed the variant since 2014: six classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000497839	SCV003828103	uncertain significance	not provided	2019-05-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000497839	SCV004562154	likely benign	not provided	2023-10-13	criteria provided, single submitter	clinical testing