Submissions for variant NM_000088.4(COL1A1):c.3766G>A (p.Ala1256Thr)

gnomAD frequency: 0.00006  dbSNP: rs148216434

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490355	SCV000267264	uncertain significance	Osteogenesis imperfecta type I	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV000877791	SCV000512687	likely benign	not provided	2019-01-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27519266, 25146735, 26901136, 21667357)
Illumina Laboratory Services, Illumina	RCV001126949	SCV001286209	benign	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001127360	SCV001286667	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001127361	SCV001286668	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). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490355	SCV001705749	likely benign	Osteogenesis imperfecta type I	2022-09-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277572	SCV002565526	uncertain significance	Ehlers-Danlos syndrome	2019-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298529	SCV002599077	benign	not specified	2022-09-23	criteria provided, single submitter	clinical testing	Variant summary: COL1A1 c.3766G>A (p.Ala1256Thr) results in a non-conservative amino acid change located in the Fibrillar collagen, C-terminal domain (IPR000885) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 250554 control chromosomes (gnomAD), predominantly at a frequency of 0.0021 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 75 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 found primarily in populations of East Asian origin. c.3766G>A has been reported in the literature in individuals affected with Osteogenesis Imperfecta, although with no evidence for familial transmission (Zhang_2012, Ho Duy_2016). In one affected compound heterozygous individual, the variant of interest was inherited from an unaffected mother and a pathogenic splice variant (COL1A1 c.1354-12G>A) was inherited from an affected father who had additional family history of Osteogenesis Imperfecta (Li_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002347820	SCV002620380	likely benign	Cardiovascular phenotype	2019-10-14	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.
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	RCV003319187	SCV003932416	uncertain significance	Hypertrophic cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000877791	SCV004563435	likely benign	not provided	2023-03-07	criteria provided, single submitter	clinical testing
Refractive Surgery Department, Bright Eye Hospital	RCV003324521	SCV004030250	likely pathogenic	Keratoconus	2023-08-27	no assertion criteria provided	clinical testing	COL1A1 encodes type I collagens, which are the major components of the corneal stroma and basement membranes. The amounts of collagen type I and type V are important for maintaining the stroma organization and shape and strength of the cornea. In this study, a heterozygous variant c.3766G>A in COL1A1 was detected in family 2, which is located in exon 18 and causes a p.A1256T amino acid change.
PreventionGenetics, part of Exact Sciences	RCV004737336	SCV005362379	uncertain significance	COL1A1-related disorder	2024-07-11	no assertion criteria provided	clinical testing	The COL1A1 c.3766G>A variant is predicted to result in the amino acid substitution p.Ala1256Thr. This variant has been reported as heterozygous in at least three patients with osteogenesis imperfecta although hearing loss status was not clearly indicated (Zhang et al. 2012. PubMed ID: 21667357; Ho Duy et al. 2016. PubMed ID: 27519266; Zhytnik et al. 2020. PubMed ID: 32166892). This variant has been reported in 0.19% of East Asian descent in gnomAD. This variant could be benign. However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.