ClinVar Genomic variation as it relates to human health

In 9 patients from 7 unrelated families of East Asian origin with subcutaneous panniculitis-like T-cell lymphoma (SPTCL; 618398), Gayden et al. (2018) identified a homozygous germline c.245A-G transition (c.245A-G, NM_032782) in the HAVCR2 gene, resulting in a tyr82-to-cys (Y82C) substitution at a highly conserved residue in the IgV domain, which is critical for terminating immune responses. The variant, which was found by whole-exome sequencing and confirmed by targeted sequencing, was found at a low frequency (0.0036) in the gnomAD database, with a higher prevalence among East Asians (minor allele frequency of 0.02104). The mutation segregated in the families from whom parental DNA was available, and heterozygous carriers were unaffected. Four individuals in the ExAC database were homozygous for the variant (3 East Asian and 1 Latino), but it was not possible to contact these individuals for phenotypic information. Heterozygosity for the variant was found in 8 of 107 control individuals from Tahiti (Polynesia) (allele frequency of 4 x 10(-2)). Haplotype analysis showed at least 12 distinct chromosomal backgrounds carrying the variant, suggesting that it is recurrent, although several patients carried a haplotype with evidence of a founder effect in the East Asian population. In patient panniculitis biopsies, mutant HAVCR2 showed abnormal intracellular aggregate staining in the peri-Golgi apparatus with limited plasma expression compared to wildtype. Peripheral monocytes from several patients showed absent HAVCR2 expression, and there was absent expression on activated CD4+ and CD8+ lymphocytes. Heterozygous carriers had an intermediate level of membrane expression. Decreased membrane expression of the mutant protein was confirmed after transfection of the mutation in HEK293 cells. In vitro functional expression studies indicated that the mutant protein was improperly folded and had disrupted posttranslational glycosylation, resulting in improper expression at the cell surface. Polprasert et al. (2019) identified a homozygous Y82C mutation in 10 unrelated patients from Thailand or Japan with SPTCL. Another patient was compound heterozygous for Y82C and a c.302C-T transition in the HAVCR2 gene, resulting in a thr101-to-ile (T101I; 606652.0003) substitution at a highly conserved residue in the IgV-like domain. The mutations were found by whole-exome sequencing and confirmed by deep sequencing. The Y82C variant had a mean allele frequency of 3.6 x 10(-3) in the gnomAD database, with enrichment among East Asians (2.1 x 10(-2)). The T101I variant had a mean allele frequency of 6.6 x 10(-3) in gnomAD, and was enriched among South Asians (1.8 x 10(-3)). Functional studies of the variants and studies of the effects of the mutation on HAVCR2 in patient cells were not performed. (less)