Table 1 Summary of results from in vitro characterization of the hitherto cloned VPS13B missense variations and update on ACMG classification.
From: Disease relevance of rare VPS13B missense variants for neurodevelopmental Cohen syndrome
Protein change (NP_689777.3)a | dbSNP | ClinVar (clinical significance) | Gnomad (minor allele frequency) | Gnomad (homozygous) | Described phenotype | Golgi localization | Golgi rescue | Applicable ACMG pathogenicity criteria | ACMG classification |
|---|---|---|---|---|---|---|---|---|---|
Wildtype | – | – | No data | No data | – | Yes | Yes | ||
Trp185Arg | – | No data | No data | No data | Cohen syndrome | n.d | n.d | ||
Phe274Val | – | No data | 0.0004442 | 0 | Autism | n.d | n.d | ||
Gly567Glu | rs141046414 | Uncertain significance | 0.0008347 | 2 | Undiagnosed genetic condition | n.d | n.d | ||
Ala590Thr | rs140601319 | Uncertain significance | 0.0001592 | 1 | Cohen syndrome | Yes | Yes | None | VUS |
Ser824Ala | rs149866274 | Uncertain significance | 0.01056 | 35 | Autism | Yes | Yes | None | VUS |
Thr1068Ile | rs61753722 | Benign/likely benign | 0.004610 | 5 | Epilepsy | n.d | n.d | ||
Lys1129Arg | rs61759485 | Conflicting interpretations | 0.000003981 | 0 | Polymorphism | n.d | n.d | ||
Pro1133Ser | rs781781537 | Likely pathogenic | No data | No data | Undiagnosed genetic condition | n.d | n.d | ||
Asp1210Tyr | – | No data | 0.00009212 | 0 | Retinal disease, CS | n.d | n.d | ||
Thr1289Ala | rs752808333 | Uncertain significance | 0.0003788 | 1 | Primary immunodeficiency disease | n.d | n.d | ||
Thr1289Ser | rs145569846 | Conflicting interpretations | no data | No data | Cohen syndrome | n.d | n.d | ||
Ile1611Asn | – | No data | 0.000003540 | 0 | Cohen syndrome | No | No | PM2, PP3, PS3, PP1sup, PP4 | LP |
Lys1682Glu | rs965365158 | No data | No data | No data | Primary immunodeficiency disease | n.d | n.d | ||
Leu2168Arg | – | Pathogenic | 0.000007075 | 0 | Cohen syndrome | No | No | PM2, PP3, PS3, PP4 | LP |
Tyr2316Cys | rs386834104 | Likely pathogenic | 0.0001768 | 0 | Cohen syndrome | No | No | PM2, PP3, PS3, PP4 | LP |
Val2456Ile | rs201963516 | Conflicting interpretations | no data | No data | Intellectual disability | n.d | n.d | ||
Gly2620Aspb | – | Conflicting interpretations | 0.000007975 | 0 | Cohen syndrome | No | No | PM2, PP3, PS3, PP1sup, PP4 | LP |
Gly2704Arg | rs767536787 | No data | 0.000003985 | 0 | Cohen syndrome/Autism | No | No | PM2, PP3, PS3 | LP |
Ser2748Leu | rs180177370 | No data | No data | No data | Cohen syndrome | No | No | PM2, PP3, PS3, PP1sup, PP4 | LP |
Ile2795Thr | – | Pathogenic | No data | No data | Cohen syndrome | Yes | Yes | PM2, PP4* | VUS |
Leu2821Ile | No data | 0.003096 | 1 | n/p | n.d | n.d | |||
Asn2968Ser | rs28940272 | Conflicting interpretations | no data | No data | Cohen syndrome | Yes | Yes | PP3, PP1sup | VUS |
Asn3088Tyr | – | No data | 0.003778 | 4 | Short stature | n.d | n.d | ||
Arg3198Trp | rs149842139 | Benign/likely benign | no data | No data | Autism | n.d | n.d | ||
Ser3303Arg | – | No data | 0.000202 | 0 | Autism/ Cohen syndrome | n.d | n.d | ||
Val3445Met | rs191174682 | Benign/likely benign | 0.000007960 | 0 | Cohen syndrome | n.d | n.d | ||
Thr3602Ile | – | No data | 0.002538 | 5 | Autism/Cohen syndrome | n.d | n.d | ||
Ala3691Thr | rs142476821 | Conflicting interpretations | No data | No data | Autism/ Cohen syndrome | n.d | n.d | ||
Pro3962Arg | – | Uncertain significance | No data | Autism | n.d | n.d |
