ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.1379G>C (p.Arg460Thr)

gnomAD frequency: 0.00023  dbSNP: rs375991767
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000819500 SCV000960164 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome 2022-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 460 of the TMEM67 protein (p.Arg460Thr). This variant is present in population databases (rs375991767, gnomAD 0.06%). This missense change has been observed in individual(s) with a nephronophthisis-related ciliopathy (PMID: 29974258). ClinVar contains an entry for this variant (Variation ID: 661970). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen RCV000999055 SCV001155455 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001161605 SCV001323497 uncertain significance Nephronophthisis 11 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV001161606 SCV001323498 uncertain significance Meckel syndrome, type 3 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV001161607 SCV001323499 uncertain significance Joubert syndrome 6 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000999055 SCV001771719 uncertain significance not provided 2022-03-15 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29974258)
Fulgent Genetics, Fulgent Genetics RCV002487823 SCV002785538 uncertain significance COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11 2022-01-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155320 SCV003844957 uncertain significance not specified 2023-02-17 criteria provided, single submitter clinical testing Variant summary: TMEM67 c.1379G>C (p.Arg460Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251348 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TMEM67 causing Joubert Syndrome And Related Disorders (0.00029 vs 0.0018), allowing no conclusion about variant significance. c.1379G>C has been reported in the literature in one individual affected with nephronophthisis-related ciliopathy. This report does 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000999055 SCV004224200 uncertain significance not provided 2023-04-19 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000999055 SCV001932743 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000999055 SCV001969695 likely benign not provided no assertion criteria provided clinical testing

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