Table 5.
Variants of unknown significance (VUS) in ALS/HMN/FTD genes (Class 3).
| Gene | Class | Variant DNA |
Variant Protein |
MAF % * | dbSNP | Additional Variants | Clinical Notes | Patient |
|---|---|---|---|---|---|---|---|---|
| OPTN | 3 | c.910C>T | p.Leu304Phe | 0%-0%-0% | (Suscep.) ATXN2: c.3000A > G (p =) het [rs140262591, MAF *: 0.2%-0.31%-0.3%] | Spinal ALS | P075 | |
| VCP | 3 | c.179A>G | p.Lys60Arg | 0%-0%-0% | (Suscep.) ATXN2: c.3322C > T (p.Pro1108Ser) het [rs140242317, MAF *: 0.04%-0.11%-0.07% ] | Slowly progressive ALS with cognitive impairment | P112 | |
| VCP | 3 | c.1696-3C>T | p.? | 0%-0.01%-0.01% | rs372638909 | Rapidly progressive ALS with cognitive impairment | P025 | |
| FIG4 | 3 | c.646G>A | p.Gly216Arg | 0%-0%-0% | rs759566206 | (Class 2) SQSTM1: c.712A > G (p.Lys238Glu) het [rs11548633, MAF *: 0.24%-0.26%-0.24%] | Progressive muscular weakness and sensory neuropathy | P105 |
| FIG4 | 3 | c.1243C>G | p.Pro415Ala | 0%-0%-0% | (Class 3) GARS1: c.302G > A (p.Arg101His) het [rs200887429, MAF *: 0.02%-0.02%-0.04%]; (Class 2) SETX: c.4660T > G (p.Cys1554Gly) het [rs112089123, MAF *: 0.58%-0.31%-0.58%] |
Spastic quadriplegia | P106 | |
| SQSTM1 | 3 | c.833C>T | p.Thr278Ile | 0%-0%-0% | rs200445838 | Myopathy | P043 | |
| UBQLN2 | 3 | c.809G>A hem | p.Arg270His | 0%-0%-0% | rs767597171 | Spinal ALS (Flail arm) | P017 | |
| SETX | 3 | c.-114-2A>G | p.? | 0.08%-0%-0% | rs560095915 | Bulbar ALS, onset 43 years | P079 | |
| SETX | 3 | c.934A>G | p.Ile312Val | 0%-0%-0% | Spinal ALS, onset 67 years | P045 | ||
| SETX | 3 | c.2344G>T | p.Val782Leu | 0%-0%-0% | (AR) ALS2: c.37G > A (p.Gly13Arg) het [rs367871772, MAF *: 0%-0.01%-0.01%] (Class 4); | Lower motor neuron involvement, onset 21 years | P071 | |
| SETX | 3 | c.3494C>G | p.Ser1165Cys | 0%-0%-0% | Spinal ALS, onset 72 years | P029 | ||
| SETX | 3 | c.4220A>G | p.Asn1407Ser | 0%-0%-0% | rs747050949 | Bulbar ALS, onset 79 years | P069 | |
| SETX | 3 | c.4957A>G | p.Lys1653Glu | 0%-0%-0% | Spinal ALS, onset 66 years | P088 | ||
| ANG | 3 | c.61C>T | p.Pro21Ser | 0%-0.02%-0.02% | rs149672657 | (HMN) TRPV4: c.1006C > T (p.Arg336Cys) het [rs781229110, MAF *: 0%-0%-0%] (Class 3); (Class 2) SQSTM1: c.712A > G (p.Lys238Glu) het [rs11548633, MAF *: 0.24%-0.26%-0.24%] (Class 2) SETX: c.3229G > A (p.Asp1077Asn) het [rs145097270, MAF *: 0.08%-0.07%-0.11%] |
Spinal ALS | P094 |
| CHMP2B | 3 | c.36T>G | p.Asp12Glu | 0%-0%-0% | (Class 2) GRN: c.264+7G > A (p = ?)het [rs60100877, MAF *: 0.5%-0.6%-0.53%] | Spinal ALS, onset 71 years | P074 | |
| ERBB4 | 3 | c.421 + 5G>A | p.? HSF: Alteration of the WT donor site, most probably affecting splicing | 0%-0%-0% | rs778195807 | - | P024 | |
| NRBB4 | 3 | c.1441A>G | p.Ile481Val | 0%-0.01%-0% | rs368860175 | Bulbar ALS, onset 70. One affected sibling | P092 | |
| MATR3 | 3 | c.1132G>A | p.Ala378Thr | 0%-0.03%-0.01% | rs201075828 | Spinal ALS, onset 37 years | P099 | |
| GARS1 | 3 | c.302G>A | p.Arg101His | 0.02%-0.02%-0.04% | rs200887429 | - | P005 | |
| GARS1 | 3 | c.302G>A | p.Arg101His | 0.02%-0.02%-0.04% | rs200887429 | Spinal ALS | P030 | |
| GARS1 | 3 | c.571A>T | p.Thr191Ser | 0%-0%-0% | rs760133861 | (Class 2) GARS1: c.803C > T (p.Thr268Ile) het [rs2230310, MAF *: 0.12%-0.48% 0.32% | Spinal ALS | P062 |
| GARS1 | 3 | c.1159G>A | p.Ala387Thr | 0%-0%-0% | rs776528885 | Bulbar ALS and FTD | P065 | |
| GRN | 3 | c.-8 + 7G>C | p? | 0%-0%-0% | Bulbar ALS | P054 | ||
| GRN | 3 | c.329G>A | p.Arg110Gln | 0.02%-0.01%-0.01% | rs375439809 | Neuroacanthocytosis | P110 | |
| GRN | 3 | c.1528C>T | p.Arg510Cys | 0%-0%-0% | rs747873577 | Spinal ALS | P034 | |
| GRN | 3 | c.1691G>A | p.Arg564His | 0%-0%-0% | Spinal ALS | P035 | ||
| MAPT | 3 | c.64G>A | p.Asp22Asn | 0%-0%-0% | rs745662662 | (AR) IGHMBP2: c.2362C > T (p.Arg788Ter) het [rs199839840, MAF *: 0%-0.01%-0% (Class5) | Spinal ALS | P059 |
| MAPT | 3 | c.319G>A | p.Gly107Ser | 0%-0%-0% | rs769901930 | Spinal ALS and mild cognitive impairment | P057 | |
| TRPV4 | 3 | c.113A>G | p.Asn38Ser | 0.02%-0%-0% | rs527355587 | (Class 2) TRPV4: c.2518G > A (p.Glu840Lys) het [rs55728855, MAF *: 0.24%-0.74%-0.63% | ALS monomelic type | P033 |
| TRPV4 | 3 | c.1496C>T | p.Pro499Leu | 0.02%-0%-0% | rs115358347 | - | P093 |
* MAF% (minor allele frequency) in 1000Genomes-Go-ESP–ExAC. Hem: hemizygous; het: heterozygous; HSF: Human Splicing Finder; (Suscep.): variants in susceptibility genes; (AR): variants in autosomal recessive genes; (HMN): variants in motor neuronopathy disease genes. het: heterozygous; (AR): variants in autosomal recessive genes.