Table 1.
INF2 variants in the 10 index patients with Charcot–Marie–Tooth disease and Focal Segmental Glomerulosclerosis.
| Family | Exon | Amino Acid | Nucleotide Change | Inheritance | gnomAD | ClinVAR | dbSNP | CADD | Reported CaAR | References | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Change | cDNA position | Zygosity | MAF | Interpre-tation | Accession | Score | Max R % | |||||
| Single FSGS phenotype MIM613237 | ||||||||||||
| 1 AI | Exon 3 | p.Gly157Arg | c.469G > C | Hetero | AD | 0 | NA | NA | NA | 25.1 | ND | NA |
| 2 AJ | Exon 3 | p.Thr161Asn | c.482C > A | Hetero | AD | 0 | NA | NA | NA- | 23.6 | ND | Tsukaguchi H, 2019 |
| 3 SH | Exon 3 | p.Leu162Pro | c.485 T > C | Hetero | AD | 0 | LP | VCV001184454.2 | NA | 25.3 | 9 | Caridi G, 2014 |
| 4 HO | Exon 4 | p.Asn202Ser | c.605A > G | Hetero | AD | 0 | LP | VCV001697256.1 | NA | 23.4 | 49 | Santin S, 2011 |
| 5 TO | Exon 4 | p.Arg218Trp | c.652C > T | Hetero | AD | 0 | P | VCV000001052.5 | rs267606878 | 25.4 | 0 | Brown E, 2010 |
| 6 KI | Exon 4 | p.Glu220Lys | c.658G > A | Hetero | de novo | 0 | P | VCV000523533.7 | rs530391015 | 24.7 | 33 | Brown E, 2010 |
| Dual CMT/FSGS phenotype MIM614455 | ||||||||||||
| 7 OK | Exon 2 | p.Leu69Pro | c.206 T > C | Hetero | mosaicism | 0 | VUS | VCV000637710.1 | rs1595163820 | 26.9 | 0 | Toyota K, 2013 |
| 8 NI | Exon 2 | p.Gly73Asp | c.218G > A | Hetero | de novo | 0 | NA | NA | NA | 26.5 | 0(Gly73Ser) | Hara M, 1984, Barua M, 2013 |
| 9 OS | Exon 2 | p.Gly73Val | c.218G > T | Hetero | ND | 0 | P | VCV000472842.6 | rs918089359 | 26.3 | 0(Gly73Ser) | Nagano C, 2020 |
| 10 YA | Exon 2 | p.Val108Asp | c.323 T > A | Hetero | de novo | 0 | VUS | VCV000637711.1 | rs1595164081 | 24.6 | 5 | Toyota K, 2013 |
INF2 variants are annotated according to the nucleotide numbering of RefSeq NM_022489.4, where the A of the ATG-translation initiation codon is designated as position 1. Population allele frequency was obtained from the public database gnomAD (genome Aggregation Database); MAF, minor allele frequency; None of these variants were found in databases of Japanese healthy controls: HGVD, human genetic variation database; ToMMo, Integrative Japanese Genome Variation Database (iJGVD) of the Tohoku University Tohoku Medical Megabank Organization. AD, autosomal dominant. Scoring of deleteriousness was determined by Combined Annotation Dependent Depletion (CADD). In ClinVar annotations, variants are classified according to recommendation by the American College of Medical Genetics and Genomics (ACMG): P, Pathogenic; LP, Likely Pathogenic; VUS, Variant of uncertain significance. Calcium-dependent cellular actin organization (CaAR) was as described in a previous study10. CaAR measured in HeLa INF2 knock-out cells is shown as the percentage of cells with Max(R) values > 14.9. The values range from 100% (in control and cells expressing benign variants) to 0% (in cells expressing pathogenic variants). CMT, Charcot–Marie–Tooth Disease, FSGS, Focal segmental glomerulosclerosis, ND, not determined, NA, not applicable.