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

gnomAD frequency: 0.00006  dbSNP: rs202036490

Total submissions: 11

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