Submissions for variant NM_000088.4(COL1A1):c.3040C>T (p.Arg1014Cys)

gnomAD frequency: 0.00001  dbSNP: rs72653170

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000420639	SCV000516589	pathogenic	not provided	2022-04-07	criteria provided, single submitter	clinical testing	Skin biopsy from an affected adult with this variant demonstrated less densely packed collagen fibrils of variable shape and size surrounded by granular material, while analysis of collagen fibrils in cultured skin fibroblasts indicated increased disulfide crosslinking (Gensure et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Located in the Gly-X-Y triple helical region of the pro-alpha1(I) chain encoded by the COL1A1 gene, where triplet glycine substitutions are the most common cause of osteogenesis imperfecta (OI). The effect of missense substitution at the X and Y positions are more difficult to predict; however, multiple variants that result in introduction of a Cys residue in pro-alpha1(I) have been reported to be pathogenic (Dalgleish, 1998); This variant is associated with the following publications: (PMID: 21249479, 22855962, 15864348, 18553566, 18704262, 17309652, 21567126, 24390061)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685879	SCV000813379	pathogenic	Osteogenesis imperfecta type I	2024-09-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1014 of the COL1A1 protein (p.Arg1014Cys). This variant is present in population databases (rs72653170, gnomAD 0.006%). This missense change has been observed in individual(s) with Caffey disease (PMID: 15864348, 17309652, 18553566, 18704262, 21249479, 21567126, 24390061). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg836Cys. ClinVar contains an entry for this variant (Variation ID: 17347). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL1A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects COL1A1 function (PMID: 15864348). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763407	SCV000894136	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form; Postmenopausal osteoporosis; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Infantile cortical hyperostosis; Ehlers-Danlos syndrome, arthrochalasia type; Osteogenesis imperfecta type I	2018-10-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000420639	SCV001474271	pathogenic	not provided	2020-05-21	criteria provided, single submitter	clinical testing	The COL1A1 c.3040C>T; p.Arg1014Cys variant (rs72653170) is reported in the literature in numerous individuals and families affected with infantile cortical hyperostosis, also called Caffey disease (Cho 2008, Gensure 2005, Kitaoka 2014, Suphapeetiporn 2007). This variant has been observed to segregate with disease in multiple families, although it exhibits incomplete penetrance (Gensure 2005, Kitaoka 2014, Suphapeetiporn 2007). In one family, the variant was found in two affected identical twins but was absent from both parents, suggesting a de novo origin (Gensure 2005). This variant is found on only two chromosomes in the Genome Aggregation Database (2/250334 alleles), indicating it is not a common polymorphism. The arginine at codon 1014 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Cho TJ et al. The c.3040C > T mutation in COL1A1 is recurrent in Korean patients with infantile cortical hyperostosis (Caffey disease). J Hum Genet. 2008;53(10):947. Gensure RC et al. A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. J Clin Invest. 2005 May;115(5):1250-7. Kitaoka T et al. Two Japanese familial cases of Caffey disease with and without the common COL1A1 mutation and normal bone density, and review of the literature. Eur J Pediatr. 2014 Jun;173(6):799-804. Suphapeetiporn K et al. Expanding the phenotypic spectrum of Caffey disease. Clin Genet. 2007 Mar;71(3):280-4.
OMIM	RCV000018889	SCV000039173	pathogenic	Infantile cortical hyperostosis	2008-07-15	no assertion criteria provided	literature only
GeneReviews	RCV000018889	SCV000054466	not provided	Infantile cortical hyperostosis		no assertion provided	literature only