Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_153704.6(TMEM67):c.2314_2322+4delATGAGTAATGTAAinsGG(p.Met772fs) variant causes a frameshift, splice donor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
TMEM67 (HGNC:28396): (transmembrane protein 67) The protein encoded by this gene localizes to the primary cilium and to the plasma membrane. The gene functions in centriole migration to the apical membrane and formation of the primary cilium. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Meckel syndrome type 3 (MKS3) and Joubert syndrome type 6 (JBTS6). [provided by RefSeq, Nov 2008]
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-93803676-ATGAGTAATGTAA-GG is Pathogenic according to our data. Variant chr8-93803676-ATGAGTAATGTAA-GG is described in ClinVar as [Pathogenic]. Clinvar id is 411583.Status of the report is criteria_provided_single_submitter, 1 stars.
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Nov 03, 2023
This variant results in the deletion of part of exon 22 (c.2314_2322+4delinsGG) of the TMEM67 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TMEM67 are known to be pathogenic (PMID: 20232449, 23559409). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Meckel-Gruber syndrome (PMID: 17160906). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 2315_2323+4del13insGG. For these reasons, this variant has been classified as Pathogenic. -