Submissions for variant NM_153704.6(TMEM67):c.1634G>A (p.Gly545Glu)

gnomAD frequency: 0.00001  dbSNP: rs267607114

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512642	SCV003257016	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 545 of the TMEM67 protein (p.Gly545Glu). This variant is present in population databases (rs267607114, gnomAD 0.0009%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 17160906). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1374). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV004808544	SCV005431853	likely pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	TMEM67: PM3:Strong, PM2, PP4