ClinVar Miner

Submissions for variant NM_001077418.3(TMEM231):c.139+47C>A

gnomAD frequency: 0.00029  dbSNP: rs200063331
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000685081 SCV000812553 pathogenic Joubert syndrome 20; Meckel syndrome, type 11 2023-09-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser83*) in the TMEM231 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM231 are known to be pathogenic (PMID: 23012439, 23349226). This variant is present in population databases (rs200063331, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with TMEM231-related conditions. ClinVar contains an entry for this variant (Variation ID: 565503). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001731886 SCV001983528 pathogenic Joubert syndrome and related disorders 2024-01-22 criteria provided, single submitter clinical testing Variant summary: TMEM231 c.248C>A (p.Ser83X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00023 in 177604 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TMEM231 causing Joubert Syndrome And Related Disorders (0.00023 vs 0.0004), allowing no conclusion about variant significance. To the best of our knowledge, c.248C>A has been not reported in the literature in individuals affected with Joubert Syndrome And Related Disorders, but in an individual with Congenital Stationary Night Blindness, this variant was reported as an additional finding, together with a pathogenic NYX variant that may fully explain the eye phenotype (Zhu_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Joubert Syndrome And Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35456422). ClinVar contains an entry for this variant (Variation ID: 565503). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV002544710 SCV003718952 likely pathogenic Inborn genetic diseases 2022-05-14 criteria provided, single submitter clinical testing The c.176C>A (p.S59*) alteration, located in exon 1 (coding exon 1) of the TMEM231 gene, consists of a C to A substitution at nucleotide position 176. This changes the amino acid from a serine (S) to a stop codon at amino acid position 59. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the available evidence, this alteration is classified as likely pathogenic.

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