Submissions for variant NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser)

gnomAD frequency: 0.00001  dbSNP: rs775883520

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000198666	SCV000255217	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-07-19	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 216826). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26092869, 27491411, 28719906). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs775883520, gnomAD 0.003%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 242 of the TMEM67 protein (p.Asn242Ser). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM67 protein function. For these reasons, this variant has been classified as Pathogenic.
UW Hindbrain Malformation Research Program, University of Washington	RCV000201726	SCV000256502	pathogenic	Joubert syndrome 6	2015-02-23	criteria provided, single submitter	research
Ambry Genetics	RCV000624166	SCV000741944	likely pathogenic	Inborn genetic diseases	2016-11-28	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000201726	SCV001164356	pathogenic	Joubert syndrome 6	2018-12-03	criteria provided, single submitter	research	The homozygous p.Asn242Ser variant in TMEM67 was identified by our study in one individual with Joubert syndrome. The p.Asn242Ser variant in TMEM67 was reported in 23 individuals (including 22 Iranians) with Joubert syndrome, segregated with disease in 22 affected relatives from 9 families (PMID: 28719906, 19574260), and has been identified in 0.002978% (1/33580) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775883520). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency and its prevalence in Iranian families with a shared haplotype suggests this is a founder variant (PMID: 28719906). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant was also reported likely pathogenic in ClinVar prior to the publication of a paper about 22 Iranians from 9 families with this variant and Joubert syndrome (Variation ID: 216826). Two additional variants at the the same position, p.Asn242Thr and p.Asn242Lys, have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 23559409, 19574260). Position 242 in the TMEM67 protein has also been reported as a glycosylation site for GlcNAc, providing additional support that a change in this position may not be tolerated (Entry: Q5HYA8) In summary, this variant meets criteria to be classified as pathogenic for Joubert syndrome in an autosomal recessive manner based on the predicted impact of a change at position 242 in TMEM67 and cosegregation with Joubertssyndrome in multiple Iranian families. ACMG/AMP Criteria applied: PM2, PP3, PM5, PM1_Supporting, PP1_Strong (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV001090385	SCV001245912	pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001090385	SCV001251690	pathogenic	not provided	2020-05-03	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814102	SCV001755382	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
3billion	RCV002283466	SCV002572798	likely pathogenic	COACH syndrome 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.91). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000216826). Different missense changes at the same codon (p.Asn242Lys, p.Asn242Thr) have been reported to be associated with TMEM67 -related disorder (PMID: 19574260 , 23559409). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV001090385	SCV002820536	pathogenic	not provided	2023-01-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26260382, 29302074, 25920555, 26092869, 30315573, 32000717, 33726816, 35032046, 28719906, 27491411)