Submissions for variant NM_000088.4(COL1A1):c.3680G>A (p.Arg1227His)

gnomAD frequency: 0.00002  dbSNP: rs543809032

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001712452	SCV000577031	likely benign	not provided	2019-01-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526752	SCV000627248	likely benign	Osteogenesis imperfecta type I	2024-12-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002455947	SCV002615267	uncertain significance	Cardiovascular phenotype	2024-01-02	criteria provided, single submitter	clinical testing	The p.R1227H variant (also known as c.3680G>A), located in coding exon 48 of the COL1A1 gene, results from a G to A substitution at nucleotide position 3680. The arginine at codon 1227 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488631	SCV004240851	likely benign	not specified	2023-12-01	criteria provided, single submitter	clinical testing	Variant summary: COL1A1 c.3680G>A (p.Arg1227His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 282806 control chromosomes. The observed variant frequency is approximately 1.26 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 benign. To our knowledge, no occurrence of c.3680G>A in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; one submitter classified it as uncertain significance, while two submitters classified it as likley benign. Based on the evidence outlined above, the variant was classified as likely benign.
Breakthrough Genomics, Breakthrough Genomics	RCV001712452	SCV005218120	likely benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV004551617	SCV004773046	uncertain significance	COL1A1-related disorder	2024-01-30	no assertion criteria provided	clinical testing	The COL1A1 c.3680G>A variant is predicted to result in the amino acid substitution p.Arg1227His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-48264135-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.