Submissions for variant NM_000089.4(COL1A2):c.3047C>A (p.Pro1016His)

gnomAD frequency: 0.00006  dbSNP: rs377278762

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723559	SCV000331314	uncertain significance	not provided	2015-06-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000723559	SCV000590226	uncertain significance	not provided	2022-03-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter 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); This variant is associated with the following publications: (PMID: 25944380, 24077912, 27535533, 34091789, 26177859)
Invitae	RCV002229738	SCV000627331	likely benign	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-11-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764736	SCV000895871	uncertain significance	Osteogenesis imperfecta with normal sclerae, dominant form; Postmenopausal osteoporosis; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Ehlers-Danlos syndrome, cardiac valvular type; Ehlers-danlos syndrome, arthrochalasia type, 2	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001162767	SCV001324732	likely benign	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 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.
Illumina Laboratory Services, Illumina	RCV001162768	SCV001324733	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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278258	SCV002565580	uncertain significance	Ehlers-Danlos syndrome	2022-05-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002446511	SCV002754001	uncertain significance	Cardiovascular phenotype	2021-11-01	criteria provided, single submitter	clinical testing	The p.P1016H variant (also known as c.3047C>A), located in coding exon 46 of the COL1A2 gene, results from a C to A substitution at nucleotide position 3047. The proline at codon 1016 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in a subject with osteogenesis imperfecta (OI) (Lindahl K et al. Eur. J. Hum. Genet., 2015 Aug;23:1042-50). This amino acid position is not well 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000723559	SCV004564169	likely benign	not provided	2023-03-03	criteria provided, single submitter	clinical testing