ClinVar

Description

Variant summary: SERPINF1 c.242C>G (p.Ser81Cys) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of 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 0.001 in 251414 control chromosomes, predominantly at a frequency of 0.0023 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in SERPINF1 causing Osteogenesis Imperfecta phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.242C>G has been reported in the literature in at-least one homozygous individual within settings of multigene panel testing among cohorts reportedly affected with Osteogenesis Imperfecta (example, Essawi_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Osteogenesis Imperfecta. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.