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Early onset or syndromic epilepsy v1.191 KRAS Rebecca Foulger Source Wessex and West Midlands GLH was added to KRAS.
Early onset or syndromic epilepsy v1.190 KRAS Rebecca Foulger Source NHS GMS was added to KRAS.
Early onset or syndromic epilepsy v1.189 KRAS Rebecca Foulger reviewed gene: KRAS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 KRAS Tracy Lester reviewed gene: KRAS: Rating: GREEN; Mode of pathogenicity: ; Publications: 21686750, 21871821 ; Phenotypes: Cardiofaciocutaneous syndrome, 615278; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.1284 RALA Konstantinos Varvagiannis gene: RALA was added
gene: RALA was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RALA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: RALA were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology
Penetrance for gene: RALA were set to unknown
Mode of pathogenicity for gene: RALA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RALA was set to GREEN
Added comment: Hiatt et al. (doi.org/10.1371/journal.pgen.1007671) report on 11 individuals (incl. a pair of monozygotic twins) from 10 unrelated families, most (10/11) with de novo mutations in RALA.

DD/ID was a prominent feature (the authors note that ID was specifically noted in 8 but could not be excluded in 3 further individuals who appear to be very young in the table). Structural brain anomalies (9/11), seizures (6/11) and common facial features were also noted.

RALA belongs to the RAS superfamily of small GTPases.

5 different de novo missense variants and 1 in-frame deletion, all within a GTP/GDP binding region of RALA (although appart in the protein primary structure) were observed. 7 occurrences of missense variants concerned Val25 and Lys128 (V25M, V25L, K128R), one Asp130 (D130G) and a further one Ser157 (S157A). The in-frame deletion concerned Ala158.

Missense variants in corresponding positions of RAS proteins (HRAS/KRAS/NRAS) have been reported in RASopathies, while the authors observed some phenotypic overlap with the latter group of disorders (DD/ID, growth delay, macrocephaly, high forehead and position of ears).

Functional studies demonstrated reduction in GTPase activity (for all variants) and altered RALA effector binding (for most reduction - in the case of S157A, increase).

Several lines of evidence are provided to show that alteration of the GTP/GTP-binding rather than a dosage effect is considered the likely mechanism. RALA is depleted in missense mutations in its GTP/GDP binding domain.

For these reasons and others (segregation studies not possible, variant observed 2x in Bravo database, phenotypic differences compared to the rest of the cohort, ROH suggesting parental consanguinity in the specific individual) the single nonsense variant (R176X) reported in the study is considered a VUS.

Seizures were a feature in most (6/11) individuals (5 different variants incl. R176X). Discordance for this feature was however noted for individuals with the same variant.

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v0.1148 KRAS Ivone Leong Marked gene: KRAS as ready
Early onset or syndromic epilepsy v0.1148 KRAS Ivone Leong Gene: kras has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1148 KRAS Ivone Leong Classified gene: KRAS as Green List (high evidence)
Early onset or syndromic epilepsy v0.1148 KRAS Ivone Leong Added comment: Comment on list classification: Promoted from amber to green as an additional report on a patient with a variant in the KRAS gene who also has seizures (PMID: 17601930).
Early onset or syndromic epilepsy v0.1148 KRAS Ivone Leong Gene: kras has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1147 KRAS Ivone Leong Publications for gene: KRAS were set to 21871821; 23059812; 16474405; 21871821
Early onset or syndromic epilepsy v0.1003 KRAS Ivone Leong Classified gene: KRAS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.1003 KRAS Ivone Leong Added comment: Comment on list classification: Cardiofaciocutaneous syndrome 2 was confirmed on both OMIM and Gene2Phenotype. One report (PMID: 16474405) found one proband with a missense variant in the KRAS gene that had seizures, and another study (PMID: 21871821) found 2 unrelated Japanese probands with missense mutations who have seizures. There is not enough evidence to promote the gene.
Early onset or syndromic epilepsy v0.1003 KRAS Ivone Leong Gene: kras has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1001 KRAS Ivone Leong Publications for gene: KRAS were set to
Early onset or syndromic epilepsy v0.1000 KRAS Ivone Leong Added comment: Comment on mode of pathogenicity: Variants cause gain-of-function effects (PMID: 21871821, 23059812).
Early onset or syndromic epilepsy v0.1000 KRAS Ivone Leong Mode of pathogenicity for gene: KRAS was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v0.982 KRAS Ivone Leong Mode of inheritance for gene: KRAS was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.964 KRAS Ivone Leong Phenotypes for gene: KRAS were changed from to Cardiofaciocutaneous syndrome 2, 615278
Early onset or syndromic epilepsy KRAS Zornitza Stark reviewed gene: KRAS
Early onset or syndromic epilepsy KRAS Sarah Leigh Added gene to panel