Submissions for variant NM_153704.6(TMEM67):c.2122G>A (p.Ala708Thr)

gnomAD frequency: 0.00002  dbSNP: rs149475825

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001060051	SCV001224712	likely pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 708 of the TMEM67 protein (p.Ala708Thr). This variant is present in population databases (rs149475825, gnomAD 0.01%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 28125082). ClinVar contains an entry for this variant (Variation ID: 854908). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TMEM67 protein function with a positive predictive value of 95%. This variant disrupts the p.Ala708 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002482047	SCV002782082	uncertain significance	COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11	2024-06-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800683	SCV005422273	uncertain significance	not specified	2024-10-14	criteria provided, single submitter	clinical testing	Variant summary: TMEM67 c.2122G>A (p.Ala708Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251312 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2122G>A has been reported in the literature in a compound heterozygous individual affected with Joubert Syndrome And Related Disorders (Vilboux_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28125082). ClinVar contains an entry for this variant (Variation ID: 854908). Based on the evidence outlined above, the variant was classified as uncertain significance.