Submissions for variant NM_000088.4(COL1A1):c.77G>A (p.Gly26Asp)

gnomAD frequency: 0.00011  dbSNP: rs151171179

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001091447	SCV001247502	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	COL1A1: PS4:Moderate, PP2, BP4, BP5, BS2
Illumina Laboratory Services, Illumina	RCV001122286	SCV001280999	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001122287	SCV001281000	uncertain significance	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 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	RCV001122288	SCV001281001	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000786920	SCV001686159	likely benign	Osteogenesis imperfecta type I	2025-01-07	criteria provided, single submitter	clinical testing
GeneDx	RCV001091447	SCV001818242	likely benign	not provided	2020-11-13	criteria provided, single submitter	clinical testing	Reported in an unrelated proband diagnosed with Osteogenesis Imperfecta, who harbored a second COL1A1 variant, phase unknown (Fuccio et al., 2011); however, no clinical details or segregation data were provided; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL1A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012).; This variant is associated with the following publications: (PMID: 21884818)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279529	SCV002565540	uncertain significance	Ehlers-Danlos syndrome	2022-05-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004027358	SCV005032209	likely benign	Cardiovascular phenotype	2024-03-05	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.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786920	SCV000925821	uncertain significance	Osteogenesis imperfecta type I	2018-12-12	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004738003	SCV005362743	uncertain significance	COL1A1-related disorder	2024-06-05	no assertion criteria provided	clinical testing	The COL1A1 c.77G>A variant is predicted to result in the amino acid substitution p.Gly26Asp. This variant was reported in three individuals with osteogenesis imperfecta, although one of these individuals had a second missense variant in this gene while another had a homozygous likely pathogenic variant in another gene (Fuccio et al 2011. PubMed ID: 21884818; Demir et al. 2021. PubMed ID: 33470886; Erbaş et al. 2021. PubMed ID: 34107839). This variant is reported in 0.068% of alleles in individuals of Latino descent in gnomAD, including >275 heterozygous individuals in the gnomADv4 database (https://gnomad.broadinstitute.org/variant/17-50201437-C-T?dataset=gnomad_r4). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.