rs386834180

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 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

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

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
COACH syndrome 1
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Meckel syndrome, type 3
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
nephronophthisis 11
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
COACH syndrome 1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
Joubert syndrome 6
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Boichis syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMEM67 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 56762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6 link	c.1046T>C	p.Leu349Ser	missense_variant	Exon 10 of 28	ENST00000453321.8	NP_714915.3	Q5HYA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 link	c.1046T>C	p.Leu349Ser	missense_variant	Exon 10 of 28	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

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

GnomAD2 exomes

AF:

0.0000200

AC:

AN:

249854

AF XY:

0.0000222

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 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

African (AFR)

AF:

0.0000300

AC:

AN:

33280

American (AMR)

AF:

0.00

AC:

AN:

44488

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39544

South Asian (SAS)

AF:

0.00

AC:

AN:

85536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0000515

AC:

AN:

1105928

Other (OTH)

AF:

0.0000499

AC:

AN:

60122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000475

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

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 05, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 10, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

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

Aug 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meckel-Gruber syndrome

Pathogenic:1

Sep 13, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome 6

Pathogenic:1

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Pathogenic:1

Mar 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 disorder

Pathogenic:1

Oct 12, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

(source)

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

MutationAssessor

Uncertain

2.4

.;M;.

PhyloP100

7.1

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

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over