Submissions for variant NM_000088.4(COL1A1):c.1249C>G (p.Pro417Ala)

dbSNP: rs72648327

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000307161	SCV000337191	likely benign	not specified	2015-11-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001711856	SCV000730525	likely benign	not provided	2020-06-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15741671, 18028452, 31061748)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000864424	SCV001005222	likely benign	Osteogenesis imperfecta type I	2025-01-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001127852	SCV001287208	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	RCV001127853	SCV001287209	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.
Illumina Laboratory Services, Illumina	RCV001127854	SCV001287210	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001127854	SCV002565122	likely benign	Osteogenesis imperfecta	2021-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002401987	SCV002668786	likely benign	Cardiovascular phenotype	2022-04-07	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	RCV000307161	SCV005726386	likely benign	not specified	2024-11-13	criteria provided, single submitter	clinical testing	Variant summary: COL1A1 c.1249C>G (p.Pro417Ala) results in a non-conservative amino acid change located in the Collagen triple helix repeat domain of 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 0.00068 in 250042 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 24 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A1 causing Osteogenesis Imperfecta phenotype (2.8e-05). To our knowledge, no occurrence of c.1249C>G in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. The following publication has been ascertained in the context of this evaluation (PMID: 15741671). ClinVar contains an entry for this variant (Variation ID: 284534). Based on the evidence outlined above, the variant was classified as likely benign.