Table 1.
UMOD variants detected in gnomAD and ADTKD
| Position (GRCh38) | rs identification | HGVS coding | HGVS protein | gnomAD AC (AF) | TOPMed AC (AF) | ALFA AC (AF) | ADTKD families | AA change | REVEL | ClinVar |
|---|---|---|---|---|---|---|---|---|---|---|
| 16:20349117:T:G | rs143248111 | c.184A > C | p.(Thr62Pro) | 99/282,046/0 (3.5 × 10−4) | 51/125,568 (4.1 × 10−4) | 47/94,922 (5.0 × 10−4) | 2 | neu, pol > neu, nonpol | 0.54 | Conflicting (B, VUS) |
| 16:20348984:C:A | rs398123697 | c.317G > T | p.(Cys106Phe)* | 2/184,308/0 (1.1 × 10−5) | 1/125,568 (8.0 × 10−6) | 1/11,176 (9.0 × 10−5) | 9 | neu, nonpol > neu, nonpol | 0.91 | Conflicting (VUS, 4× LP) |
| 16:20348975:A:T | rs780462125 | c.326T > A | p.(Val109Glu)† | 3/215,296/0 (1.4 × 10−5) | 5/125,568 (4.0 × 10−5) | 1/2,188 (4.6 × 10−4) | 1 | neu, nonpol > neg, pol | 0.76 | LP |
| 16:20348763:G:C | rs187555378 | c.538C > G | p.(Leu180Val) | 578/174,180/8 (3.3 × 10−3) | 1,277/12,5568 (1.0 × 10−2) | 8/11,174 (7.2 × 10−4) | 1 | neu, nonpol > neu, nonpol | 0.51 | B |
| 16:20348594:G:A | rs1447458978 | c.707C > T | p.(Pro236Leu)‡ | 1/207,972/0 (4.8 × 10−6) | / | / | 7 | neu, nonpol > neu, nonpol | 0.97 | P/LP |
| 16:20348551:G:T | rs1475702916 | c.750C > A | p.(His250Gln)§ | 1/223,344/0 (4.5 × 10−6) | / | / | 1 | pos, pol > neu, pol | 0.80 | / |
| 16:20348480:T:C | rs375848177 | c.821A > G | p.(Tyr274Cys)¶ | 1/244,864/0 (4.1 × 10−6) | 1/125,568 (8.0 × 10−6) | / | 1 | neu, pol > neu, nonpol | 0.96 | / |
| 16:20341262:G:A | rs143583842 | c.1406C > T | p.(Thr469Met) | 203/282,716/1 (7.2 × 10−4) | 81/125,568 (6.5 × 10−4) | 82/88,416 (9.3 × 10−4) | 2 | neu, pol > neu, nonpol | 0.56 | Conflicting (LB, 2× VUS) |
Overlapping UMOD variants with frequencies in the general population, the number of ADTKD families, and in silico pathogenicity scores are shown. The 3 most frequent UMOD missense variants further studied are indicated in bold. GnomAD (18) allele counts (ACs) are reported as ACs/total allele number/number of homozygotes (with AF in parentheses). The theoretical maximum tolerated AC for high-effect UMOD variants (pathogenic [P]) in gnomAD is estimated to be one (46) (SI Appendix has more details). Annotation and in silico analyses were performed using the VarSome platform (51) and Ensembl VEP considering ENST00000302509.8 as the reference transcript. For REVEL (19), a score >0.5 corresponds to a sensitivity of 0.75 and a specificity of 0.89 for P variants in the training dataset. ClinVar was last accessed April 2021. GRCh38, Genome Reference Consortium Human Build 38; rs, Reference SNP; HGVS, Human Genome Variation Society; AA, amino acid; ClinVar, Clinical Variations database; VEP, Variant Effect Predictor; neu, neutral; nonpol, non polar; pol, polar; neg, negative; pos, positive; ALFA, National Center for Biotechnology Information (NCBI) Allele Frequency Aggregator (https://www.ncbi.nlm.nih.gov/snp/docs/gsr/alfa/); B, benign; LB, likely benign; LP, likely pathogenic; TOPMed, Trans-Omics for Precision Medicine Program (50).
*Using CRISPR-Cas9 gene editing, a mouse model with the homologous mutation was created that showed intracellular and secreted UMOD aggregates, but characterization of ER stress or kidney function was not shown (52). In vitro trafficking of this UMOD isoform was similar to the wild type (in vitro score of one) (20).
†In the reported ADTKD family, the index patient displayed kidney failure at 20 to 24 y, and intracellular UMOD accumulation was described in the kidney biopsy. However, two first-degree relatives were heterozygous for p.Val109Glu without presenting hyperuricemia or CKD. In vitro analysis indicated ER retention of the UMOD isoform (43, 53).
‡An in vitro score of three indicates considerable ER retention in stably transfected MDCK cells (20).
§The 45- to 49-y-old index patient had classical presentation (CKD, gout with low fractional excretion of uric acid (FEUA), small kidneys, and reduced urinary UMOD levels). However, the family history was negative (mutation status in parents was not known), and her clinically unaffected child carried the variant but was only 10 to 14 y old at the time of investigation (54).
¶The index patient was described with features not classically associated with ADTKD: early-onset CKD, microhematuria, mental retardation, and hearing impairment. The kidney biopsy showed glomerulosclerosis and tubular atrophy. Two siblings and a grandparent have been reported as affected (44).