Submissions for variant NM_000088.4(COL1A1):c.1984-5C>A

gnomAD frequency: 0.00249  dbSNP: rs66592376

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177437	SCV000229293	benign	not specified	2015-05-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000177437	SCV000512685	benign	not specified	2017-12-20	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	RCV000514224	SCV000609655	likely benign	not provided	2017-08-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000177437	SCV000612896	benign	not specified	2017-07-17	criteria provided, single submitter	clinical testing
Invitae	RCV000989945	SCV000627192	benign	Osteogenesis imperfecta type I	2024-01-31	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659353	SCV000781164	uncertain significance	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000989945	SCV001140688	likely benign	Osteogenesis imperfecta type I	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514224	SCV001157099	benign	not provided	2023-09-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001125582	SCV001284667	likely benign	Ehlers-Danlos syndrome, arthrochalasia type	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	RCV001127681	SCV001287018	uncertain significance	Infantile cortical hyperostosis	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 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	RCV001127682	SCV001287019	uncertain significance	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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000177437	SCV001467769	benign	not specified	2020-12-08	criteria provided, single submitter	clinical testing	Variant summary: COL1A1 c.1984-5C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.003 in 244168 control chromosomes, predominantly at a frequency of 0.0051 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 180 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 a benign polymorphism. Though the variant c.1984-5C>A (also called as IVS29-5C>A) has been reported in the literature in individuals affected with Osteogenesis Imperfecta (Venturi_2006, Schleit_2015), no strong evidence for causality was provided. These reports therefore do not provide unequivocal conclusions about association of the variant with Osteogenesis Imperfecta. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (1x), likely benign (3x) or benign (5x). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000514224	SCV002545948	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	COL1A1: BP4, BS1, BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001127682	SCV002565144	benign	Osteogenesis imperfecta	2021-09-17	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277393	SCV002565484	benign	Ehlers-Danlos syndrome	2021-09-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415762	SCV002718341	likely benign	Cardiovascular phenotype	2021-11-04	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.
PreventionGenetics, part of Exact Sciences	RCV004552992	SCV004797357	likely benign	COL1A1-related disorder	2019-04-09	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Molecular Genetics, Royal Melbourne Hospital	RCV003993859	SCV004812440	likely benign	Ehlers-Danlos/osteogenesis imperfecta syndrome	2023-08-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000177437	SCV001809020	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000177437	SCV001929784	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000514224	SCV001975323	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000514224	SCV002036129	likely benign	not provided		no assertion criteria provided	clinical testing