ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.958A>T (p.Ser320Cys)

gnomAD frequency: 0.00089  dbSNP: rs111619594
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Preventiongenetics, part of Exact Sciences RCV003389624 SCV000316352 uncertain significance TMEM67-related condition 2023-05-09 criteria provided, single submitter clinical testing The TMEM67 c.958A>T variant is predicted to result in the amino acid substitution p.Ser320Cys. The TMEM67 c.653G>C and c.958A>T variants have been reported in cis phase in a patient with Bardet-Biedl syndrome who was homozygous for a CEP290 nonsense variant (Leitch et al 2008. PubMed ID: 18327255). This variant is reported in 0.30% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-94793190-A-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Eurofins Ntd Llc (ga) RCV000725926 SCV000340550 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing
GeneDx RCV000725926 SCV000617746 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 (G218A) on the same allele (in cis), and had a different genetic etiology for the phenotype (Leitch et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20981092, 20690115, 27336129, 20301537, 34426522, 18327255)
Invitae RCV001085857 SCV001003485 likely benign Familial aplasia of the vermis; Meckel-Gruber syndrome 2024-01-23 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001158404 SCV001320043 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 RCV001158405 SCV001320044 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.
Illumina Laboratory Services, Illumina RCV001158406 SCV001320045 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001198570 SCV001369559 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.
Baylor Genetics RCV001333012 SCV001525489 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].
CeGaT Center for Human Genetics Tuebingen RCV000725926 SCV004156006 uncertain significance not provided 2023-10-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003488318 SCV004241182 uncertain significance not specified 2023-12-15 criteria provided, single submitter clinical testing Variant summary: TMEM67 c.958A>T (p.Ser320Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 251056 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TMEM67 causing Joubert Syndrome 6 (0.00039 vs 0.004), allowing no conclusion about variant significance. c.958A>T has been reported in the literature in individuals affected with Bardet-Biedl syndrome and Cohen syndrome, in which pathogenic variants from other genes were identified to be the genetic cause (example, Dixon-Salazar_2012, Leitch_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Joubert Syndrome 6. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect as the Zebrafish modeling and the rescuing phenotype of developmental delay are not appropriate for evaluating this variant (Leitch_2008). The following publications have been ascertained in the context of this evaluation (PMID: 22700954, 18327255). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=7, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM RCV000001444 SCV000021594 risk factor Bardet-Biedl syndrome 14, modifier of 2008-04-01 no assertion criteria provided literature only
GeneReviews RCV000234830 SCV000292016 not provided Nephronophthisis no assertion provided literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000725926 SCV001952951 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000725926 SCV001963774 uncertain significance not provided no assertion criteria provided clinical testing

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