Submissions for variant NM_001367721.1(CASK):c.1915C>T (p.Arg639Ter)

dbSNP: rs137852815

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255325	SCV000322221	pathogenic	not provided	2016-07-07	criteria provided, single submitter	clinical testing	The R639X pathogenic variant in the CASK gene has been reported previously as a de novo pathogenic variant in association with intellectual disability, microcephaly, and pontine and cerebellar hypoplasia in a female (Najm et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R639X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret R639X as a pathogenic variant consistent.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000012286	SCV002507062	pathogenic	Syndromic X-linked intellectual disability Najm type	2022-05-04	criteria provided, single submitter	curation	The hemizygous p.Arg639Ter variant in CASK was identified by our study in 1 individual with mental retardation and microcephaly with pontine and cerebellar hypoplasia. Trio exome analysis showed this variant to be de novo. The variant has been reported in 1 Turkish individual with mental retardation and microcephaly with pontine and cerebellar hypoplasia (PMID: 19165920), but was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 11530) as pathogenic by OMIM and GeneDx. This nonsense variant leads to a premature termination codon at position 639, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the CASK gene is an established disease mechanism in mental retardation and microcephaly with pontine and cerebellar hypoplasia. In summary, this variant meets criteria to be classified as pathogenic for mental retardation and microcephaly with pontine and cerebellar hypoplasia in an X-linked dominant manner based on the predicted impact of the variant, and occurrences in affected individuals while absent from control populations. ACMG/AMP Criteria applied: PVS1, PM2, PS4_supporting, PS2 (Richards 2015).
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798721	SCV002818263	pathogenic	Intellectual disability	2024-10-04	criteria provided, single submitter	research	PVS1, PS2, PM2
OMIM	RCV000012286	SCV000032520	pathogenic	Syndromic X-linked intellectual disability Najm type	2008-09-01	no assertion criteria provided	literature only