ClinVar Miner

Submissions for variant NM_016464.5(TMEM138):c.287A>G (p.His96Arg) (rs387907132)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000423402 SCV000521218 likely pathogenic not provided 2017-07-21 criteria provided, single submitter clinical testing A published H96R variant that is likely pathogenic has been identified in the TMEM138 gene. The H96R variant has been reported previous in association with Joubert syndrome and related disorders (JSRD) (Lee et al., 2012; Szymanska et al., 2012). Funcational studies suggest that the H96R variant results in an unstable protein (Lee et al., 2012). The H96R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the H96R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000024187 SCV001433669 likely pathogenic Joubert syndrome 16 2020-09-14 criteria provided, single submitter clinical testing A homozygous missense variation in exon 3 of the TMEM138 gene that results in the amino acid substitution of Arginine for Histidine at codon 96 was detected. The observed variant c.287A>G (p.His96Arg) lies in the transmembrane protein 138 domain of the TMEM138 protein and has previously been reported in patients affected with Joubert syndrome (Lee et al. 2012). The variant is classified as likely pathogenic in ClinVar database. The variant has not been reported in the 1000 genomes and has a minor allele frequency of 0.002% in the gnomAD database. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
OMIM RCV000024187 SCV000045478 pathogenic Joubert syndrome 16 2012-02-24 no assertion criteria provided literature only

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