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

gnomAD frequency: 0.00089  dbSNP: rs111619594

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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)
Labcorp Genetics (formerly Invitae), Labcorp	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001333012	SCV004807924	uncertain significance	COACH syndrome 1	2024-03-29	criteria provided, single submitter	clinical testing
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
PreventionGenetics, part of Exact Sciences	RCV004528064	SCV000316352	uncertain significance	TMEM67-related disorder	2024-09-04	no assertion criteria provided	clinical testing	The TMEM67 c.958A>T variant is predicted to result in the amino acid substitution p.Ser320Cys. This variant in TMEM67 (also known as MKS3) has been reported in cis with TMEM67 c.653G>C in a patient with Bardet-Biedl syndrome, who also carried a homozygous 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. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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