ClinVar Genomic variation as it relates to human health

The S81C variant has been reported in the homozygous state in a patient with recurrent and multiple fractures but normal sclerae and teeth (Essawi et al., 2017). The S81C variant is observed in 251/277180 (0.0906%) alleles in large population cohorts, including in the apparent homozygous state in multiple apparently unaffected individuals (Lek et al., 2016). The S81C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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.

SERPINF1: BS1

BS1, BS2, PP3, PS4_supporting

Phenotype not severe enough for osteogenesis imperfecta.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).