Submissions for variant NM_016464.5(TMEM138):c.306_307dup (p.Arg103fs)

dbSNP: rs771224190

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001999542	SCV002288281	pathogenic	Joubert syndrome 16	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg103Hisfs*24) in the TMEM138 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 60 amino acid(s) of the TMEM138 protein. This variant is present in population databases (rs771224190, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TMEM138-related conditions. ClinVar contains an entry for this variant (Variation ID: 1505578). This variant disrupts a region of the TMEM138 protein in which other variant(s) (p.Ala126Thr) have been determined to be pathogenic (PMID: 22282472). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001999542	SCV005400454	likely pathogenic	Joubert syndrome 16	2024-09-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 16 (MM#614465). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated TMEM138 domain (DECIPHER). (I) 0703 - Other truncating variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Arg103Thrfs*33) has been classified as pathogenic in ClinVar. p.(Arg103Alalfs*23) has been classified as pathogenic in ClinVar and in the literature in two homozygous individuals with Joubert syndrome (PMID: 26489029, 32404165). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. ClinVar contains one likely pathogenic entry. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign