ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.514C>T (p.Arg172Ter)

gnomAD frequency: 0.00002  dbSNP: rs765468645
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000613872 SCV000713496 likely pathogenic Meckel-Gruber syndrome 2018-01-31 criteria provided, single submitter clinical testing The p.Arg91X (NM_001142301.1 c.271C>T) (also described as NM_153704.5:c.514C>T p .Arg172X) variant in TMEM67 has been reported in 1 compound heterozygous individ ual with Meckel syndrome (Matson 2016). It has been identified in 1/24020 Africa n chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.o rg; rs765468645). This nonsense variant leads to a premature termination codon a t position 91, which is predicted to lead to a truncated or absent protein. Bial lelic loss of function of the TMEM67 gene is an established disease mechanism in Meckel syndrome. This alteration is then predicted to lead to a truncated or ab sent protein. In summary, although additional studies are required to fully esta blish its clinical significance, the p.Arg91X variant is likely pathogenic for M eckel syndrome in an autosomal recessive manner based on a predicted variant eff ect and its occurrence in an affected individual.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000627005 SCV000747708 pathogenic Iris coloboma; Nystagmus; Generalized hypotonia; Cerebellar vermis hypoplasia 2017-01-01 criteria provided, single submitter clinical testing
Invitae RCV001860256 SCV002235529 pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome 2023-06-20 criteria provided, single submitter clinical testing This variant is present in population databases (rs765468645, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg172*) in the TMEM67 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM67 are known to be pathogenic (PMID: 20232449, 23559409). This premature translational stop signal has been observed in individual(s) with Meckel-Gruber syndrome (PMID: 26729329). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 506012).
Fulgent Genetics, Fulgent Genetics RCV002506454 SCV002808714 pathogenic COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11 2022-03-19 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital RCV003236585 SCV003935005 pathogenic Meckel syndrome, type 3 2023-06-23 criteria provided, single submitter clinical testing The heterozygous variant c.514C>T (p.Arg172*) has been identified on couple carrier screening. The couple has a bad obstetric history. This variant can be associated with the fetal phenotype of renal cysts and occipital encephalocele in the previous fetus. This stop gain variant is predicted to cause NMD in the gene TMEM67 where loss of function is a known mechanism (PVS1_very strong). 86 pathogenic null variants have been reported in this gene so far. The population frequency in gnomAD (aggregated) is 0.0011% (PM2_moderate). This has been previously reported PMID 26729329 (PP5_supporting).

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