ClinVar Genomic variation as it relates to human health

The p.Cys246Ser variant in LIPH has been reported in the homozygous or compound heterozygous state in >15 individuals with hypotrichosis and segregated with dis ease in 4 affected relatives from 4 families (Shimomura 2009, Shinkuma 2010, Yos himasu 2011, Tanahashi 2013, Hayashi 2014, Ito 2015). This variant has been desc ribed as a common founder variant in the Japanese population. This variant has b een identified in 0.2% (37/17248) of East Asian chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID: 225403). Although this variant has been seen in the g eneral population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p .Cys246Ser variant may impact protein function (Shinkuma 2010); however, these t ypes of assays may not accurately represent biological function. Computational p rediction tools and conservation analysis suggest that the p.Cys246Ser variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for hypotrichosis in an autosomal recessive manner based upon presenc e in affected individuals, segregation studies, and functional evidence. ACMG/AM P Criteria applied: PM3_VeryStrong, PP1_Moderate, PP3, PS3_Supporting.

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225403, PMID:19892526). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.956>=0.6). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001552). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change is predicted to replace cysteine with serine at codon 246 of the LIPH protein, p.(Cys246Ser). The cysteine residue is invariant across species (100 vertebrates, UCSC), and forms a crucial disulphide bond in the lipase domain. There is a large physicochemical difference between cysteine and serine. The variant is present in a large population cohort at a frequency of 0.016% (rs201249971, 39/251,346 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.15% in the East Asian population (36/18,394 alleles). The variant is a Japanese founder variant that has been identified in the homozygous state and compound heterozygous with a second pathogenic allele in multiple individuals with autosomal recessive woolly hair/hypotrichosis, and segregates with disease in at least one family (PMID: 19892526, 20213768). Additionally, in vitro functional assays show complete abolition of hydrolytic activity and no ability to activate P2Y5 for the variant (PMID: 20213768). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM1, PS3_Supporting, PP1, PP3.