rs386834182
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The ENST00000453321.8(TMEM67):c.1319G>A(p.Arg440Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000818 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R440W) has been classified as Pathogenic.
Frequency
Consequence
ENST00000453321.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMEM67 | NM_153704.6 | c.1319G>A | p.Arg440Gln | missense_variant | 13/28 | ENST00000453321.8 | NP_714915.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMEM67 | ENST00000453321.8 | c.1319G>A | p.Arg440Gln | missense_variant | 13/28 | 1 | NM_153704.6 | ENSP00000389998 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152052Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251216Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135786
GnomAD4 exome AF: 0.0000855 AC: 125AN: 1461768Hom.: 0 Cov.: 31 AF XY: 0.0000756 AC XY: 55AN XY: 727196
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74386
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 02, 2024 | Published functional studies in a knockout mouse model demonstrate a damaging effect with abolished binding to Wnt5a (PMID: 26035863); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17377820, 19058225, 20232449, 26729329, 26275793, 19466712, 30266093, 17397051, 36090483, 26035863) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 06, 2023 | PP1_strong, PP3, PM2, PM3, PS3_supporting, PS4_moderate - |
Meckel syndrome, type 3 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 440 of the TMEM67 protein (p.Arg440Gln). This variant is present in population databases (rs386834182, gnomAD 0.01%). This missense change has been observed in individuals with Meckel–Gruber syndrome (PMID: 17377820, 17397051). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56764). 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. - |
Joubert syndrome and related disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2021 | Variant summary: TMEM67 c.1319G>A (p.Arg440Gln) results in a 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 6e-05 in 251216 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TMEM67 causing Joubert Syndrome and Related Disorders (0.0018), allowing no conclusion about variant significance. The variant, c.1319G>A, has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Joubert Syndrome and Related Disorders (Consugar_2007, Khaddour_2007, Tallila_2009, Brancati_2009, Iannicelli_2010), including segregation evidence in some families (Consugar_2007, Tallila_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that the variant abolished binding to Wnt5a, and failed to restore the de-regulated Wnt/beta-catenin signaling in Tmem67 -/- mouse embryonic fibroblasts (Abdelhamed_2015).Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS, likely pathogenic or pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at