Submissions for variant NM_000088.4(COL1A1):c.334-5C>A

gnomAD frequency: 0.00035  dbSNP: rs115997082

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000333833	SCV000404206	uncertain significance	Infantile cortical hyperostosis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000362772	SCV000404207	benign	Osteogenesis imperfecta	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000271447	SCV000404208	benign	Ehlers-Danlos syndrome, arthrochalasia type	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000497393	SCV000589932	uncertain significance	not provided	2017-06-15	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the COL1A1 gene. The c.334-5 C>A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 0.2-0.3% alleles from individuals of African ancestry in large population cohorts, indicating it may be a rare benign variant in this population (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.334-5 C>A variant occurs at a nucleotide position that is not conserved across species. Additionally, in silico splice prediction algorithms are inconclusive as to whether or not this variant damages the splice acceptor site in intron 3. While other splice site variants in the COL1A1 gene have been reported in HGMD in association with COL1A1-related disorders (Stenson et al., 2014), in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001514913	SCV001722875	benign	Osteogenesis imperfecta type I	2024-12-12	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252095	SCV002522729	likely benign	See cases	2021-06-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: BS1, BP4
Ambry Genetics	RCV002323529	SCV002606662	likely benign	Cardiovascular phenotype	2021-01-25	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.
CeGaT Center for Human Genetics Tuebingen	RCV000497393	SCV002822412	benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	COL1A1: BP4, BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV004549712	SCV004767214	likely benign	COL1A1-related disorder	2020-03-19	no assertion criteria provided	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).