rs386834180
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_153704.6(TMEM67):c.1046T>C(p.Leu349Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000411 in 1,606,212 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 (★★).
Frequency
Consequence
NM_153704.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249854Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134962
GnomAD4 exome AF: 0.0000420 AC: 61AN: 1454026Hom.: 0 Cov.: 27 AF XY: 0.0000456 AC XY: 33AN XY: 723692
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74364
ClinVar
Submissions by phenotype
Meckel syndrome, type 3 Pathogenic:2
This fetus is heterozygous for a known pathogenic variant, c.1046T>C (p.Leu349Ser), in the TMEM67 gene. This variant (dbSNP: rs386834180) has been previously reported in fetuses with Meckel syndrome in the literature (Iannicelli et al 2010 Hum Mutat 31:E1319-1331; Khaddour et al 2007 Hum Mutat 28:523-524). Functional studies have shown that this variant is pathogenic (Abdelhamed et al 2015 Disease models & Mechanisms 8:527-541) -
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not provided Pathogenic:2
Published functional studies demonstrate that the L349S variant impacts protein function (Abdelhamed et al., 2015; 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: 21068128, 19574260, 28844315, 17397051, 21866095, 19466712, 20232449, 23559409, 26092869, 26729329, 31589614, 34731008, 32160518, 26035863) -
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Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 349 of the TMEM67 protein (p.Leu349Ser). This variant is present in population databases (rs386834180, gnomAD 0.005%). This missense change has been observed in individual(s) with TMEM67-related ciliopathies (PMID: 17397051, 19574260, 20232449, 21068128, 26729329). 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: 56762). 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%. Experimental studies have shown that this missense change affects TMEM67 function (PMID: 26035863). For these reasons, this variant has been classified as Pathogenic. -
Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 Pathogenic:1
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Meckel-Gruber syndrome Pathogenic:1
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Joubert syndrome 6 Pathogenic:1
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TMEM67-related disorder Pathogenic:1
Across a selection of the available literature, the TMEM67 c.1046T>C (p.Leu349Ser) missense variant has been reported in at least seven individuals from six families with Joubert syndrome or Meckel syndrome (Khaddour et al. 2007; Iannicelli et al. 2010; Chaki et al. 2011; Bachmann-Gagescu et al. 2015). Four of the cases were terminated fetuses that met the diagnostic criteria for Meckel syndrome. In three of these cases, including one sibling pair, the variant was observed in a compound heterozygous state with a truncating variant; in the fourth case, it was found in a homozygous state. In the remaining three cases, it was observed in a compound heterozygous state with a second missense variant in individuals with Joubert syndrome. Parental inheritance of the variant was demonstrated in two of the compound heterozygous cases. The p.Leu349Ser variant was absent from at least 410 control chromosomes and is reported at a frequency of 0.000060 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies conducted in embryonic fibroblasts from Tmem67 knockout mice showed that unlike the wildtype protein, p.Leu349Ser TMEM67 was unable to rescue the impaired canonical Wnt/β-catenin signalling or deficient response to Wnt5a observed in the Tmem67-deficient cells (Abdelhamed et al. 2015). Based on the collective evidence, the p.Leu349Ser variant is classified as pathogenic for TMEM67-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at