Submissions for variant NM_001044385.3(TMEM237):c.52C>T (p.Arg18Ter)

gnomAD frequency: 0.00006  dbSNP: rs199469707

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000024179	SCV000832031	pathogenic	Joubert syndrome 14	2024-09-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg18*) in the TMEM237 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM237 are known to be pathogenic (PMID: 22152675). This variant is present in population databases (rs199469707, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Joubert syndrome (PMID: 22152675, 22981120). It is commonly reported in individuals of Hutterite ancestry (PMID: 22152675, 22981120). ClinVar contains an entry for this variant (Variation ID: 31180). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000024179	SCV000996142	pathogenic	Joubert syndrome 14	2018-05-04	criteria provided, single submitter	clinical testing	This nonsense variant found in exon 2 of 13 is predicted to result in loss of normal protein function. This variant has been previously reported as a homozygous change in ten Canadian Hutterite patients with intellectual disability, a characteristic facial appearance, encephalocele, coloboma, renal disease, and additional features consistent with a diagnosis of a Joubert syndrome related disorder (PMID: 22152675, 17603801). The variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (15/275258) and thus is presumed to be rare. Based on the available evidence, c.52C>T (p.Arg18Ter) variant is classified as pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000024179	SCV002503680	pathogenic	Joubert syndrome 14	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature termination codon at position 18 in exon 2 (of 13) of TMEM237 ,p.(Arg18*). It is expected to result in an absent or disrupted protein product, and loss of function is the established mechanism of disease for this gene (PMID: 22152675). The variant is present in a large population cohort at a frequency of 0.006%, which is consistent with a recessive condition (rs199469707, 16/278,360 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in individuals with Joubert syndrome, and segregates with the condition in the homozygous state in multiple related Canadian Hutterite families. Fibroblast cell lines from homozygous cases show loss of TMEM237 expression, and defective ciliogenesis and pairing of centrioles (PMID: 22152675). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong, PM2_Supporting, PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265568	SCV002548123	pathogenic	Joubert syndrome and related disorders	2022-05-06	criteria provided, single submitter	clinical testing	Variant summary: TMEM237 c.52C>T (p.Arg18X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar. The variant allele was found at a frequency of 6.1e-05 in 247028 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TMEM237 causing Joubert Syndrome And Related Disorders (6.1e-05 vs 0.0004), allowing no conclusion about variant significance. The variant was found at an 8% carrier frequency rate within the Hutterite communities of Canada and the Northern United States, indicating a founder effect for the variant. Subsequently, c.52C>T has been reported in the literature in multiple homozygous individuals affected with Joubert Syndrome And Related Disorders from Hutterite communities (Huang_2011). The variant was also found in at least one compound heterozygous, presumably non-Hutterite individual (Clark_2019). These data indicate that the variant is very likely to be associated with disease. Huang_2011 has shown that fibroblasts homozygous for the variant have defects in ciliogenesis with no detectable ciliated cells as seen via microscopy. Huang_2011 also showed that the variant causes large reductions (98%) in TMEM237 transcripts and fibroblasts with the variant had dysregulated Wnt signaling. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000024179	SCV002557323	pathogenic	Joubert syndrome 14	2022-02-02	criteria provided, single submitter	clinical testing	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 14 (MIM#614424). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as homozygous in many related Hutterite individuals with severe Joubert syndrome related disorder (PMIDs: 17603801, 22152675). It has been described as a founder variant in Hutterite individuals (PMID: 31710777). It has also been reported as pathogenic in ClinVar, however ethnicity of those individuals were not provided. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies using patient fibroblast line showed defective ciliogenesis and pairing of centrioles, and reduced TMEM237 expression level (PMID: 22152675). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV000024179	SCV003828095	pathogenic	Joubert syndrome 14	2021-12-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001701641	SCV005385347	pathogenic	not provided	2024-04-25	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 31964843, 36788019, 22981120, 27247959, 25697177, 22152675, 31019026)
Fulgent Genetics, Fulgent Genetics	RCV000024179	SCV005654494	pathogenic	Joubert syndrome 14	2023-12-21	criteria provided, single submitter	clinical testing
OMIM	RCV000024179	SCV000045470	pathogenic	Joubert syndrome 14	2012-10-05	no assertion criteria provided	literature only
GeneReviews	RCV000034999	SCV000058637	pathologic	Familial aplasia of the vermis	2012-03-29	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701641	SCV001930943	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001701641	SCV001958174	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001701641	SCV001969324	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748538	SCV005361113	pathogenic	TMEM237-related disorder	2024-03-19	no assertion criteria provided	clinical testing	The TMEM237 c.52C>T variant is predicted to result in premature protein termination (p.Arg18*). This variant is documented as causative for Joubert syndrome (Huang et al. 2011. PubMed ID: 22152675). Approximately 6% of Canadian Hutterites are carriers for this pathogenic variant (Huang et al. 2011. PubMed ID: 22152675). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TMEM237 are expected to be pathogenic. This variant is interpreted as pathogenic.