Submissions for variant NM_000089.4(COL1A2):c.3313G>A (p.Gly1105Ser)

gnomAD frequency: 0.00066  dbSNP: rs139851311

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000286436	SCV000470623	likely benign	Osteogenesis imperfecta	2017-04-27	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	RCV000342187	SCV000470624	likely benign	Ehlers-danlos syndrome, arthrochalasia type, 2	2017-04-27	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.
GeneDx	RCV000432079	SCV000520904	likely benign	not specified	2017-10-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513852	SCV000609869	likely benign	not provided	2017-03-06	criteria provided, single submitter	clinical testing
Invitae	RCV002229990	SCV000627335	likely benign	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2024-01-31	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659381	SCV000781192	uncertain significance	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513852	SCV001155152	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513852	SCV001471501	uncertain significance	not provided	2023-10-26	criteria provided, single submitter	clinical testing	The COL1A2 c.3313G>A; p.Gly1105Ser variant (rs139851311) is reported in the literature in several individuals affected with osteogenesis imperfecta or Ehlers-Danlos Syndrome, though it was not demonstrated to cause disease (Junkiert-Czarnecka 2022, Mei 2022, Stephen 2014, Zhang 2012). This variant is also reported in ClinVar (Variation ID: 360968). It is found in the South Asian population with an overall allele frequency of 0.24% (73/30610 alleles) in the Genome Aggregation Database. The glycine at codon 1105 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.783). It is unclear if this glycine residue is incorporated into the collagen triple helix domain. While the population frequency of this variant is inconsistent with disease, given the lack of clinical and functional data, the significance of the p.Gly1105Ser variant is uncertain at this time. References: Junkiert-Czarnecka A et al. Next-Generation Sequencing of Connective Tissue Genes in Patients with Classical Ehlers-Danlos Syndrome. Curr Issues Mol Biol. 2022 Mar 25;44(4):1472-1478. PMID: 35723357. Mei Y et al. Comparing Clinical and Genetic Characteristics of De Novo and Inherited COL1A1/COL1A2 Variants in a Large Chinese Cohort of Osteogenesis Imperfecta. Front Endocrinol (Lausanne). 2022 Jul 14;13:935905. PMID: 35909573. Stephen J et al. Mutation spectrum of COL1A1 and COL1A2 genes in Indian patients with osteogenesis imperfecta. Am J Med Genet A. 2014 Jun;164A(6):1482-9. PMID: 24668929. Zhang ZL et al. The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta. J Bone Miner Metab. 2012 Jan;30(1):69-77. PMID: 21667357.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000286436	SCV002564792	likely benign	Osteogenesis imperfecta	2019-12-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278617	SCV002565583	uncertain significance	Ehlers-Danlos syndrome	2021-02-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004022060	SCV005032181	likely benign	Cardiovascular phenotype	2020-03-05	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.