ClinVar

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 38 (MIM#619476). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Sanger sequencing of cDNA obtained from an individual with orofaciodigital syndrome demonstrated exon 8 skipping. This results in a premature termination codon (p.(Asp439Glyfs*6), also annotated as p.(Asp439Glyfs*5) in the literature) which is predicted to undergo nonsense-mediated decay (NMD, PMID: 26643951). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0702 - Other premature termination variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Multiple NMD-predicted variants have been reported in affected individuals and as likely pathogenic/pathogenic (PMID: 34523780, ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been reported de novo in an individual with orofaciodigital syndrome who is compound heterozygous with another nonsense variant, NM_014804.2:c.1891A>T; p.(Lys631*) (PMID: 26643951). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The KIAA0753 protein was hardly detectable in the immortalised cells of an individual who also has a nonsense variant. The recruitment of its partner proteins onto the centrosomes was also reduced (PMID: 26643951). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign