ClinVar Genomic variation as it relates to human health

The DPYS c.1137C>A (p.Ser379Arg) missense variant has been reported in one study in which it was found in a total of four unrelated individuals with dihydropyrimidinase deficiency, including three in a homozygous state and one in a compound heterozygous state (van Kuilenburg et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000190 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies in E. coli demonstrated the p.Ser379Arg variant results in significantly reduced levels of protein expression and residual enzyme activity of less than 1% (van Kuilenburg et al. 2010). Protein modelling suggested that the Ser379 residue is highly conserved and the p.Ser379Arg variant may result in enzyme misfolding (van Kuilenburg et al. 2010). Expression in 293FT cells found the p.Ser379Arg variant exhibited reduced protein levels, oligomer formation, and a shorter half-life compared to wildtype (Hishinuma et al. 2017). Based on the evidence, the p.Ser379Arg variant is classified as likely pathogenic for dihydropyrimidinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The c.1137C>A;p.(Ser379Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 372797; PMID: 20362666; 28642038) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28642038) - PS3_supporting. The variant is present at low allele frequencies population databases (rs201258823– gnomAD 0.001511%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Ser379Arg) was detected in trans with a Pathogenic variant (PMID: 20362666; 28642038) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic

ACMG classification criteria: PS3 supporting, PM2 moderated, PM3 moderated, PP3 supporting

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DPYS function (PMID: 20362666, 28642038). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DPYS protein function. ClinVar contains an entry for this variant (Variation ID: 372797). This missense change has been observed in individuals with clinical features of dihydropyrimidinase deficiency (PMID: 20362666). This variant is present in population databases (rs201258823, gnomAD 0.02%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 379 of the DPYS protein (p.Ser379Arg).

This sequence change is predicted to replace serine with arginine at codon 379 of the DPYS protein (p.Ser379Arg). The serine residue is highly conserved (100 vertebrates, UCSC), and is located in the amidohydrolase domain. There is a large physicochemical difference between serine and arginine. The variant is present in a large population cohort at a frequency of 0.01%, which is consistent with a recessive condition (PM2; rs201258823, 28/282,580 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified homozygous and compound heterozygous with a second allele in at least four dihydropyrimidinase deficiency cases with a variable phenotype and elevated levels of dihydrouracil, dihydrothymine, uracil, and thymine in urine and plasma samples (PM3, PP4; PMID: 20362666). Additionally, the variant impairs enzyme activity in in vitro functional assays (PS3_Supporting; PMID: 20362666, 28642038). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PM3, PS3_Supporting, PP3, PP4.

Published functional studies demonstrate a damaging effect with reduced or absent activity of protein function and lower expression level compared to wild type (PMID: 20362666, 28642038); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20362666, 32707991, 34426522, 31589614, 28642038, 38199782)