rs386834180

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_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

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.09

Variant links:

Genes affected

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]

TMEM67 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_153704.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.838

PP5

Variant 8-93781725-T-C is Pathogenic according to our data. Variant chr8-93781725-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93781725-T-C is described in Lovd as [Likely_pathogenic]. Variant chr8-93781725-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6 linkuse as main transcript	c.1046T>C	p.Leu349Ser	missense_variant	10/28	ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8 linkuse as main transcript	c.1046T>C	p.Leu349Ser	missense_variant	10/28	1	NM_153704.6	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249854

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134962

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000420

AC:

AN:

1454026

Hom.:

Cov.:

AF XY:

0.0000456

AC XY:

AN XY:

723692

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000515

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000766

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meckel syndrome, type 3

Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Sep 05, 2018	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) -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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. -

TMEM67-Related Disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 12, 2017

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/Î²-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. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 23, 2021

- -

Meckel-Gruber syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 13, 2013

- -

Joubert syndrome 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UW Hindbrain Malformation Research Program, University of Washington

Feb 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.46

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;D;.

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

T;T;T

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.95

.;P;.

Vest4

0.93, 0.89

MutPred

0.57

.;Gain of catalytic residue at L349 (P = 0.0598);.;

MVP

1.0

MPC

0.64

ClinPred

0.94

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over