ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.653G>C (p.Gly218Ala)

gnomAD frequency: 0.00006  dbSNP: rs202036490
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519954 SCV000617745 uncertain significance not provided 2023-03-31 criteria provided, single submitter clinical testing Observed in an individual in published literature who was also found to have another TMEM67 variant (S320C) on the same allele (in cis), and had a different genetic etiology for the phenotype (Leitch et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20690115, 19574260, 18327255, 34426522)
Illumina Laboratory Services, Illumina RCV001165118 SCV001327287 uncertain significance Nephronophthisis 11 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001165119 SCV001327288 uncertain significance Joubert syndrome 6 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001165120 SCV001327289 uncertain significance Meckel syndrome, type 3 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001198569 SCV001369558 uncertain significance RHYNS syndrome 2019-10-02 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
Institute of Human Genetics, University of Leipzig Medical Center RCV001165120 SCV001440695 uncertain significance Meckel syndrome, type 3 2019-01-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001333011 SCV001525488 uncertain significance COACH syndrome 1 2019-12-26 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797744 SCV002041838 uncertain significance not specified 2023-12-15 criteria provided, single submitter clinical testing Variant summary: TMEM67 c.653G>C (p.Gly218Ala) 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 0.00016 in 250962 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TMEM67 causing Joubert Syndrome And Related Disorders (0.00016 vs 0.0018), allowing no conclusion about variant significance. c.653G>C has been reported in the literature in at-least one individual affected with Bardet-Biedel syndrome who harbored a different homozygous variant (p.Glu1903*) in the CEP290 gene (Leitch_2008). Of note, this variant was reported in cis with another variant p.Ser320Cys in the MKS3 gene (MKS3 is the legacy gene name for TMEM67). The authors reported this variant as a "mildly hypomorphic" variant by live embryo analysis. The exact in-vivo implications of these findings are unclear.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. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001857955 SCV002175409 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome 2022-09-27 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 218 of the TMEM67 protein (p.Gly218Ala). This variant is present in population databases (rs202036490, gnomAD 0.02%). This missense change has been observed in individual(s) with TMEM67-related condtions (PMID: 18327255, 19574260). ClinVar contains an entry for this variant (Variation ID: 449519). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects TMEM67 function (PMID: 18327255). 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.
Fulgent Genetics, Fulgent Genetics RCV002476053 SCV002781910 uncertain significance COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11 2022-04-17 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000519954 SCV004156005 uncertain significance not provided 2023-10-01 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV001333011 SCV004807923 uncertain significance COACH syndrome 1 2024-03-29 criteria provided, single submitter clinical testing

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