Submissions for variant NM_000088.4(COL1A1):c.2932C>T (p.Pro978Ser)

gnomAD frequency: 0.00019  dbSNP: rs193922153

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000608881	SCV000052225	likely benign	not specified	2019-02-06	criteria provided, single submitter	clinical testing	Variant summary: The variant, COL1A1 c.2932C>T (p.Pro978Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 276226 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A1 causing Osteogenesis Imperfecta phenotype (2.8e-05), strongly suggesting that the variant is benign. The variant, c.2932C>T has been reported in the literature in individuals affected with Osteogenesis Imperfecta and Thoracic Aortic Aneurysm/Aortic Dissection (Pollitt_2006, Weerakkody_2018). These reports however do not provide unequivocal conclusions about association of the variant with Osteogenesis Imperfecta. Co-occurrence with another pathogenic variant (in cis) has been reported (COL1A1, c.2644 C>T (p.R882X)), for this variant, further providing a supporting evidence for its benign role. This other variant (p.R882X) segregated with disease in this family. Furthermore, as it lies upstream of this variant (p.P978S), the authors concluded that it is unlikely to affect the resultant phenotype in this family. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2X likely benign and 1X Uncertain significance). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV000537025	SCV000627217	likely benign	Osteogenesis imperfecta type I	2024-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001535421	SCV000715752	likely benign	not provided	2020-04-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29543232, 27050224, 16786509)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680480	SCV000807858	likely benign	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001125486	SCV001284560	likely benign	Osteogenesis imperfecta	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001125487	SCV001284561	uncertain significance	Infantile cortical hyperostosis	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001125488	SCV001284562	benign	Ehlers-Danlos syndrome, arthrochalasia type	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276575	SCV002565500	uncertain significance	Ehlers-Danlos syndrome	2018-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433474	SCV002750185	uncertain significance	Cardiovascular phenotype	2023-12-13	criteria provided, single submitter	clinical testing	The p.P978S variant (also known as c.2932C>T), located in coding exon 40 of the COL1A1 gene, results from a C to T substitution at nucleotide position 2932. The proline at codon 978 is replaced by serine, an amino acid with similar properties. This variant has been reported to occur in cis with a COL1A1 nonsense alteration in an individual from an osteogenesis imperfecta cohort, and was also detected in an individual with multiple fractures (Pollitt R et al. Hum Mutat, 2006 Jul;27:716; Aya KL et al. JBJS Case Connect;9:e0317). This variant was also detected in two individuals with aortic aneurysm; however, details were limited (Weerakkody R et al. Genet Med, 2018 11;20:1414-1422). This amino acid position is 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.
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000607797	SCV000731242	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection		no assertion criteria provided	research