Variant: NM_003159.2(CDKL5):c.119C>T (p.Ala40Val)

CA121521

11502 (ClinVar)

Gene: CDKL5

Condition: CDKL5 disorder

Inheritance Mode: X-linked inheritance

UUID: 0e323081-868b-43b4-974c-8893a942d274

HGVS expressions

NM_003159.2:c.119C>T
NM_003159.2(CDKL5):c.119C>T (p.Ala40Val)
ENST00000623535.2:c.119C>T
ENST00000635828.1:c.119C>T
ENST00000637881.1:c.119C>T
ENST00000674046.1:c.119C>T
ENST00000379989.6:c.119C>T
ENST00000379996.7:c.119C>T
ENST00000463994.4:c.119C>T
ENST00000623364.3:c.119C>T
ENST00000623535.1:n.119C>T
ENST00000624700.3:c.119C>T
NM_001037343.1:c.119C>T
NM_001323289.1:c.119C>T
NM_001323289.2:c.119C>T
NM_001037343.2:c.119C>T
NM_003159.3:c.119C>T
NC_000023.11:g.18564496C>T
CM000685.2:g.18564496C>T
NC_000023.10:g.18582616C>T
CM000685.1:g.18582616C>T
NC_000023.9:g.18492537C>T
NG_008475.1:g.143892C>T

Pathogenic

• Met criteria codes: PM2_Supporting PS2_Very Strong PS4 PP3 PM1

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The p.Ala40Val variant in CDKL5 has been reported in at least 4 unconfirmed de novo occurrences in patients with CDKL5 disorder (PMID 27779742, 17993579, 22678952, 19793311) (PM6_VS). It is also reported in the mosaic state in a male patient with CDKL5 disorder (PMID 25819767) and therefore confirmed to be de novo (PS2). The p.Ala40Val variant has been observed in at least 10 other individuals with CDKL5 disorder (27779742, 25819767, 17993579, 22678952, 19793311, 21309761, 19780792) (PS4). The variant is absent in gnomAD (PM2_supporting). The variant is located in a well-characterized (ATP binding region: aa 19-43) functional domain of CDKL5 (PMID: 28544139, 17993579, 23064044, 29264392) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Ala40Val in CDKL5 is classified as Pathogenic based on the ACMG/AMP criteria (PM6_very strong, PS2, PS4_strong, PM1, PM2_supporting, PP3).

Met criteria codes

• PM2_Supporting: The p.Ala40Val variant is absent in gnomAD and ExAC (PM2_supporting)
• PS2_Very Strong: Reported in the mosaic state in a male patient with CDKL5 disorder (PMID 25819767) and therefore confirmed to be de novo (PS2). PM6_VS: The p.Ala40Val variant in CDKL5 has been reported in at least 4 unconfirmed de novo occurrences in patients with CDKL5 disorder (PMID 27779742, 17993579, 22678952, 19793311). While the cases involved did not have parental relationships confirmed (PM6), they did reach the very strong threshold for this type of evidence as defined by the Rett/AS VCEP, and this criterion is being used as a proxy since PM6_very strong is not currently available.
• PS4: PS4_S: The p.Ala40Val variant has been observed in at least 10 other individuals with CDKL5 disorder (27779742, 25819767, 17993579, 22678952, 19793311, 21309761, 19780792)
• PP3: Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3)
• PM1: The variant is located in a critical domain of CDKL5 (ATP binding region: aa 19-43)(PMID: 28544139,17993579) (PM1)

Approved on: 2021-03-30

Published on: 2021-05-17