ClinVar Miner

Submissions for variant NM_000088.4(COL1A1):c.3652G>A (p.Ala1218Thr)

dbSNP: rs72656337
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001058312 SCV001222872 pathogenic Osteogenesis imperfecta type I 2022-07-25 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1218 of the COL1A1 protein (p.Ala1218Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 24891183, 28173822, 29669177, 31447884). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 853496). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001058312 SCV002557861 pathogenic Osteogenesis imperfecta type I 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with osteogenesis imperfecta types I-IV, and other conditions (OMIM). Variants resulting in a truncated protein are known to have a loss of function effect on protein, while missense variants affecting the G-X-Y triple helix motif have a dominant negative effect (PMID: 27509835, 12362985). Variants affecting the procollagen cleavage site residues result in a unique high bone mass osteogenesis imperfecta phenotype (PMID: 29669177). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic severity in affected individuals of the same family can vary across generations (PMID: 32166892). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position, p.(Ala1218Asp), has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional procollagen C-peptide cleavage site. Residues Ala1218 and Asp1219 form the site at which the collagen C-terminal propeptide is cleaved, and variants affecting these residues result in impaired collagen processing (PMID: 21344539). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The variant p.(Ala1218Pro) has been reported as pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in multiple unrelated individuals in ClinVar and the literature, typically in the context of a high bone mass osteogenesis imperfecta phenotype (PMID: 29669177, 24891183, 28173822, 31447884). (SP) 0901 - This variant has strong evidence for segregation with disease. In multiple unrelated families, this variant has segregated in affected members (PMID: 29669177, 24891183, 28173822). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant resulted in impaired collagen processing in skin fibroblast cultures from affected individuals (PMID: 29669177). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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