Table 4.
Missense and 5′UTR variants and their likely pathogenicity in main study cohort. (Reference sequence used for mutation names NM_000267.3).
| Inherited | Times seen in study cohort | Variant | Type | Exon | Segregation analysis | In silico analysis | Classification of pathogenicity1 |
|---|---|---|---|---|---|---|---|
| Yes | 1 | c.139T > C p.(Ser47Pro) | missense | 2 | Seen in 1 individual- no segregation studies done | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 3- Unknown pathogenicity |
| No | 1 | c.412G > C p.(Ala138Pro) | missense | 4 | Seen in 1 individual- not detected in parents | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 4- Likely pathogenic |
| No | 1 | c.581T > C p.(Leu194Pro) | missense | 5 | Seen in 1 individual- not detected in parents | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 4- Likely pathogenic |
| No | 1 | c.988G > C p.(Ala330Pro) | missense | 9 | Seen in 1 individual- no segregation studies done | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 3- Unknown pathogenicity |
| Yes | 1 | c.1658A > G p.(His553Arg) | missense | 15 | Seen in 3 individuals- appeared to segregate with NF1 features in 1st family & not detected in parents in 2nd family, no segregation studies done in 3rd family | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 4- Likely pathogenic |
| Yes | 1 | c.1808T > G p.(IIe603Arg) | Missense | 16 | Seen in 1 individual- no segregation studies done | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 3- Unknown pathogenicity |
| No | 1 | c.2329T > A p.(Trp777Arg) | Missense | 20 | Seen in 2 individuals- no segregation studies done in 1st family, not detected in parents in 2nd study family | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 4- Likely pathogenic |
| Yes | 1 | c.2339C > A p.(Thr780Lys) | Missense | 20 | Seen in 1 individual- no segregation studies done | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 3- Unknown pathogenicity |
| Yes | 1 | c.2530C > T p.(Lys844Phe) | Missense | 21 | Mosaic with heterozygous mutation in daughter so likely pathogenic | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 4 Likely pathogenic |
| No | 1 | c.2540T > C p.(Leu847Pro) | 21 | Seen in 2 individuals- no segregation studies done in 1st family, not detected in 1 parent in 2nd study family | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 4- Likely pathogenic (Also reported in an NF1 patient inFahsold et al. (2000) | |
| Yes | 1 | c.2543G > A p.(Gly848Glu) | Missense | 21 | Seen in 1 individual- appeared to segregate with NF1 features in the family | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 3- Unknown pathogenicity |
| Yes | 1 | c.2870A > T p.(p.Asn957Ile) | Missense | 22 | Seen in 1 individual- appeared to segregate with NF1 features in the family | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 3- Unknown pathogenicity |
| Yes | 1 | c.3044T > C p.(Leu1015Pro) | Missense | 23 | Seen in 1 individual- Did NOT appear to segregate with NF1 symptoms in the family | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 3- Unknown pathogenicity |
| Yes | 1 | c.3047G > A p.(Cys1016Tyr) | Missense | 23 | Seen in 1 individual- appeared to segregate with NF1 symptoms in the family | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 3- Unknown pathogenicity |
| Yes | 1 | c.3251C > A p.(Pro1084His) | Missense | 25 | Seen in 1 individual on a DNA screen- appeared to segregate with NF1 symptoms in the family | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 3- Unknown pathogenicity |
| Yes | 1 | c.3447G > A p.(Met1149Ile) | Missense | 26 | Seen in 2 individuals- appeared to segregate with NF1 symptoms in 1st family, no segregation studies done in 2nd family | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 4- Likely pathogenic de novo in Griffiths et al. (2007) |
| No | 1 | c.3610C > G p.(Arg1204GIy) | Missense | 27 | Seen in 2 individuals- not detected in parents in 1st study family, no segregation studies done in 2nd family | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 4 Likely pathogenic |
| No | 1 | c.3649G > T p.(Asp1217Tyr) | Missense | 27 | Seen in 1 individual- no segregation studies done | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 3- Unknown pathogenicity |
| Yes | 1 | c.3827G > A p.(Arg1276Gln) | Missense | 28 | Seen in 2 individuals- no segregation studies done in 1st family, appeared to segregate with Watson syndrome symptoms in 2nd family | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 4- Likely pathogenic |
| No | 1 | c.4016T > G p.(Leu1339Arg) | Missense | 30 | Seen in 1 individual- not detected in parents | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 4- Likely pathogenic |
| No | 1 | c.4172G > C p.(Arg1391Thr) | Missense | 32 | Seen in 2 individuals- not detected in 1 parent in 1st family, no segregation studies done in 2nd family | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 3- Unknown pathogenicity |
| No | 1 | c.4173A > T p.(Arg1391Ser) | Missense | 32 | Seen in 1 individual- no segregation studies done | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 4- Likely pathogenic (Functional studies in Upadhyaya et al. (1997) |
| No | 1 | c.4288A > G p.(Asn1430Asp) | Missense | 33 | Seen in 1 individual- no segregation studies done | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 4- Likely pathogenic (located within the NF1 RAS GAP domain. shown to be deleterious to RAS interaction in vitro) Ahmadian et al. (2003) |
| Yes | 1 | c.4306A > G p.(Lys1436Glu) | Missense | 33 | Seen in 2 individuals- no segregation studies done | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 4- Likely pathogenic (de novo in Valero et al. (2011) |
| No | 1 | c.4715T > C p.(Phe1572Ser) | Missense | 36 | Seen in 1 individual- no segregation studies done | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 3- Unknown pathogenicity |
| Yes | 1 | c.4805T > C p.(Leu1602Pro) | Missense | 37 | Seen in 1 individual- no segregation studies done | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 3-Unknown pathogenicity |
| Yes | 1 | c.4986C > G p.(Asn1662Lys) | Missense | 37 | Seen in 1 individual- no segregation studies done | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 3-Unknown pathogenicity |
| No | 1 | c.5450C > G p.(Ser1817Cys) | Missense | 38 | Seen in 1 individual- no segregation studies done | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 3-Unknown pathogenicity |
| Yes | 1 | c.5681T > G p.(Leu1894Arg) | Missense | 39 | Seen in 1 individual- appeared to segregate with NF1 features in the family | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 3-Unknown pathogenicity |
| No | 1 | c.6947T > C p.(Leu2316Pro) | Missense | 47 | Seen in 1 individual- not detected in parents | Affects an evolutionarily conserved amino-acid residue, gave conflicting results on whether it is likely to be disruptive to normal function | Class 4-Likely pathogenic |
| Yes | 1 | c.6950T > C p.(Leu2317Pro) | Missense | 47 | Seen in 2 individuals- not detected in parents in 1st family, no segregation studies done in 2nd family | Affects an evolutionarily conserved amino-acid residue and is predicted to disrupt normal function | Class 4-Likely pathogenic |
| Yes × 2 | 2 | c.-272G > A | 5′ UTR | Seen in 2 individuals- appeared to segregate with NF1 features in both families, | Class 4-Likely pathogenic | ||
| Yes | 1 | c.-272G > C, NF1 RNA NORMAL | 5′ UTR | Seen in 1 individual- appeared to segregate with NF1 symptoms in the family | Class 3-Unknown pathogenicity | ||
| No × 1 Yes × 1 |
2 | c.-273A > C | 5′ UTR | Seen in 2 individuals- not detected in parents or unaffected sister in 1st family, no segregation studies done in 2nd family | Class 4-Likely pathogenic | ||
| No | 1 | c.-280C > T | 5′ UTR | Seen in 1 individual- no segregation studies done | Class 3-Unknown pathogenicity |
1
Classification of pathogenicity follows those proposed by Plon et al. (2008),Wallis et al. (2013) and Richards et al. (2015).