Submissions for variant NM_000088.4(COL1A1):c.3755G>A (p.Arg1252His)

gnomAD frequency: 0.00004  dbSNP: rs371904584

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001127362	SCV001286669	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.
Illumina Laboratory Services, Illumina	RCV001127363	SCV001286670	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	RCV001127364	SCV001286671	benign	Ehlers-Danlos syndrome, arthrochalasia type	2017-05-22	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856661	SCV002132830	benign	Osteogenesis imperfecta type I	2025-01-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276632	SCV002565524	uncertain significance	Ehlers-Danlos syndrome	2021-08-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002348571	SCV002622190	uncertain significance	Cardiovascular phenotype	2023-08-07	criteria provided, single submitter	clinical testing	The p.R1252H variant (also known as c.3755G>A), located in coding exon 48 of the COL1A1 gene, results from a G to A substitution at nucleotide position 3755. The arginine at codon 1252 is replaced by histidine, an amino acid with highly similar properties. In one study, this variant co-occurred with a complex rearrangement reportedly resulting in complete allelic loss of COL3A1 and COL5A2 in an individual with suspected vascular Ehlers-Danlos syndrome (Weerakkody RA et al. Genet. Med., 2016 11;18:1119-1127). This amino acid position is not 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.
GeneDx	RCV003222227	SCV003918266	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005236625	SCV005885919	likely benign	not specified	2025-02-19	criteria provided, single submitter	clinical testing	Variant summary: COL1A1 c.3755G>A (p.Arg1252His) results in a non-conservative amino acid change in 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 4.4e-05 in 250618 control chromosomes. The observed variant frequency is approximately 1.56 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A1 causing Osteogenesis Imperfecta/Ehlers-Danlos Syndrome phenotype (2.8e-05). c.3755G>A has been reported in the presumed heterozygous state in complex with a large rearrangment across other collagen genes in the literature in at least 1 individual affected with clinical features of vascular Ehlers-Danlos Syndrome, without strong evidence for causality (example, Weerakkody_2016). These report(s) do not provide unequivocal conclusions about association of the variant with COL1A1-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 891837). Based on the evidence outlined above, the variant was classified as likely benign.