Table 5.
Genetic features of patients with SCN1A variants
| Patient | Sex | Pheno-type | Genomic coordinates (NC_000002.11) | Nucleotide (c.DNA) (NM_006920.6) | Protein (NP_008851.3) | Exon | Variant type | Protein domain | Inheritance | Family history | gnomAD v2.1.1 frequency | ACMG | Reported |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | M | GEFS+ | g.166915152G>T | c.311C>A | p.Ala104Asp | 2 | Missense | N-terminus | De novo | − | − | Likely pathogenic (PM1, PM2, PP2, PP3) |
Yes (ClinVar ID: 567303) |
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| 2 | F | DS | g.166930130A>C | c.2>G | p.Met1? | 1 | Initiation codon variant | N-terminus | De novo | − | − | Pathogenic (PVS1, PM2, PP3) | This paper |
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| 3 | F | DS | g.166909392G>A | c.664C>T | p.Arg222* | 5 | Nonsense | DI-S4 | De novo | − | − | Pathogenic (PVS1, PM2, PP3, PP5) | Yes (ClinVar ID: 12889) |
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| 4 | F | DS | g.166909392G>A | c.664C>T | p.Arg222* | 5 | Nonsense | DI-S4 | De novo | − | − | Pathogenic (PVS1, PM2, PP3, PP5) | Yes (ClinVar ID: 12889) |
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| 5 | F | GEFS+ | g.166903464G>A | c.1193C>T | p.Thr398Met | 9 | Missense | DI-S5S6 loop | Paternal | Father: FS+, behavioral disorder | 0.00002124 | Likely pathogenic (PM1, PM2, PP2, PP3) | Yes (ClinVar ID: 206762) |
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| 6 | M | DS | g.166897824T>G | c.2299A>C | p.Ile767Leu | 13 | Missense | DI-DII linker | De novo | − | − | Likely pathogenic (PM1, PM2, PP2, PP3) | This paper |
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| 7 | F | DS | g.166897740C>T | c.2415+1G>A | Splice-site | DII-S2 | De novo | − | − | Pathogenic (PVS1, PM2, PP3, PP5) | Yes (ClinVar ID: 801805) |
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| 8 | F | DS | g.166894396G>A | c.2803C>T | p.Arg935Cys | 15 | Missense | DII-S5S6 loop | De novo | Brother: SGS | − | Pathogenic (PM1, PM2, PM5, PP2, PP3, PP5) | Yes (ClinVar ID: 68604) |
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| 9 | F | GEFS+ | g.166892703T>C | c.3284A>G | p.Tyr1095Cys | 16 | Missense | DII-DIII linker | Maternal | Mother: FS | 0.000003978 | VUS (PM2, PP2, PP3) | Yes (ClinVar ID: 964594) |
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| 10 | F | DS | g.166866246G>A | c.3985C>T | p.Arg1329* | 20 | Nonsense | DIII-S4 | De novo | − | − | Pathogenic (PVS1, PM2, PP3, PP5) | Yes (ClinVar ID: 206816) |
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| 11 | F | DS | g.166859094T>C | c.4172A>G | p.Asn1391Ser | 21 | Missense | DIII-S5S6 loop | De novo | − | − | Likely pathogenic (PM1, PM2, PM5, PP2) |
Yes (ClinVar ID: 449374) |
|
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| 12 | M | DS | g.166848041T>C | c.5744A>G | p.Glu1915Gly | 26 | Missense | C-terminus | De novo | − | − | Likely pathogenic (PM1, PM2, PM5, PP2, PP3) |
This paper |
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| 13 | F | GEFS+ | g.166847987C>T | c.5798G>A | p.Arg1933Gln | 26 | Missense | C-terminus | Maternal | Mother: FS | 0.000007982 | VUS (PM1, PM2, PP2) | This paper |
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| 14 | M | DS | g.166854548C>T | c.4476G>A | p.Lys1492Lys | 23 | Synonymous (splice-site) | DIII-DIV linker | De novo | − | − | Likely pathogenic (PVS1, PM2, BP4) |
Yes (ClinVar ID: 426654) |
|
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| 15 | M | GEFS+ | g.166848129G>C | c.5656C>G | p.Arg1886Gly | 26 | Missense | C-terminus | Paternal | Father: FS | − | VUS (PM2, PP2, PP3) | This paper |
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| 16 | M | DS | g.166859091 TTATTCACG>CA |
c.4167_4175del-CGTGAATAAinsTG | p.Asn1391Ilefs*5 | 21 | Frameshift | DIII-S5S6 loop | De novo | − | − | Pathogenic (PVS1, PM2, PP3) | This paper |
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| 17 | M | DS | g.166904136C>T | c.1170+1G>A | Splice-site | DI-S5S6 loop | De novo | − | − | Pathogenic (PVS1, PM2, PP3, PP5) | Yes (ClinVar ID: 381570) |
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| 18 | F | GEFS+ | g.166912954A>G | c.440T>C | p.Met147Thr | 3 | Missense | DI-S1 | Maternal | Mother: FS | − | Likely pathogenic (PM1, PM2, PP2, PP3) |
This paper |
DS, Dravet syndrome; GEFS+, genetic epilepsy with febrile seizures plus; FS, febrile seizure; FS+, febrile seizure plus; SGS, secondary generalized seizure; ACMG, American College of Medical Genetics and Genomics; VUS, variant of uncertain significance; gnomAD, genome aggregation database.