ClinVar Genomic variation as it relates to human health

Variant summary: SERPINF1 c.271_279dupGCCCTCTCG (p.Ala91_Ser93dup) results in an in-frame duplication that is predicted to duplicate three amino acids into the encoded protein. The variant allele was found at a frequency of 5.6e-05 in 251326 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SERPINF1 causing Osteogenesis Imperfecta (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.271_279dupGCCCTCTCG has been reported in the literature as a biallelic homozygous or compound heterozygous genotype in multiple individuals affected with Osteogenesis Imperfecta (example, Tucker_2012, Rauch_2014, Al-Jallad_2015, Caparros-Martin_2016, Li_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Al-Jallad_2015). The most pronounced variant effect results in intracellular degradation, not transported along the secretory pathway resulting in decreased collagen type I deposition and mineralization, as well as approximately 4% of normal pigment-epithelium derived factor (PEDF) secretion in fibroblast cultures from a homozygous individual. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant, c.271_279dup, results in the insertion of 3 amino acid(s) of the SERPINF1 protein (p.Ala91_Ser93dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758551389, gnomAD 0.009%). This variant has been observed in individual(s) with osteogenesis imperfecta (PMID: 22528245, 28116328). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1224470). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SERPINF1 function (PMID: 25868797). For these reasons, this variant has been classified as Pathogenic.

Published functional studies demonstrate a damaging effect with reduction of protein expression and excretion (PMID: 25868797); In-frame duplication of 3 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 27796462, 28689307, 22528245, 25127091, 27509835, 28725987, 25086671, 25868797, 28116328, 34426522, 34627339, 37425194, 37270749)