8-93795970-T-C

Position:

chr8-93795970-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_153704.6(TMEM67):c.1843T>C(p.Cys615Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,613,072 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 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 7.25

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 8-93795970-T-C is Pathogenic according to our data. Variant chr8-93795970-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93795970-T-C is described in Lovd as [Likely_pathogenic]. Variant chr8-93795970-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6 linkuse as main transcript	c.1843T>C	p.Cys615Arg	missense_variant	18/28	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 linkuse as main transcript	c.1843T>C	p.Cys615Arg	missense_variant	18/28	1	NM_153704.6	ENSP00000389998	P1

Frequencies

GnomAD3 genomes

AF:

0.0000919

AC:

AN:

152276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

251362

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000904

AC:

132

AN:

1460796

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

726766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000157

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2023	Published functional studies demonstrate C615R results in improper localization of the TMEM67 protein within cells (Gunay-Aygun et al., 2009; Abdelhamed et al., 2015); 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: 19778711, 19508969, 19540516, 26035863, 21866095, 19466712, 21068128, 23559409, 26673778, 28125082, 10508989, 25729630, 29956005, 29146704, 29974258, 32574212, 27491411, 26092869, 20607301, 28497568, 19574260, 20232449, 25920555, 32939031, 34356094, 34958143, 35627109, 36090483) -

Joubert syndrome 6

Pathogenic:3

Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 10, 2019	A heterozygous missense variant, NM_153704.5(TMEM67):c.1843T>C, has been identified in exon 18 of 28 of the TMEM67 gene. The variant is predicted to result in a major amino acid change from cysteine to arginine at position 615 of the protein (NP_714915.3(TMEM67):p.(Cys615Arg)). The cysteine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the meckelin transmembrane functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0142% (40 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic and segregated with disease in several families with TMEM67-related ciliopathies (ClinVar). Transfected IMCD3 cells displayed impaired protein localization within the mid-cell region, and did not localize to the apical cell surface (Gunay-Aygun, M., et al. (2009)). Subsequent analysis of parental samples indicated this variant was maternally inherited. Based on current information, this variant has been classified as PATHOGENIC. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2009	- -

TMEM67-related disorder

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	Across a selection of available literature, the TMEM67 c.1843T>C (p.Cys615Arg) missense variant has been identified in a homozygous state in seven patients and in a compound heterozygous state in at least 11 patients with TMEM67-related disorders, which include the phenotypically overlapping disorders nephronophthisis, Joubert syndrome, and Meckel syndrome (Otto et al. 2009; Tallili et al. 2009; Gunay-Aygun et al. 2009; Seeman et al. 2010; Halbritter et al. 2013). The p.Cys615Arg variant was absent from 484 controls and is reported at a frequency of 0.00043 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in cell lines demonstrated that the p.Cys615Arg variant prevents the localization of the protein to cilia and disrupts the ability of TMEM67 to regulate Wnt signaling (Gunay-Aygun et al. 2009; Abdelhamed et al. 2015). Based on the collective evidence, the p.Cys615Arg 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. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 24, 2024	The TMEM67 c.1843T>C variant is predicted to result in the amino acid substitution p.Cys615Arg. This variant has been reported in the compound heterozygous or homozygous state in multiple individuals with TMEM67-related disorders, including Meckel syndrome, Joubert syndrome, and nephronophthisis (Tallila et al. 2009. PubMed ID: 19466712; Otto et al. 2009. PubMed ID: 19508969; Chaki et al. 2011. PubMed ID: 21866095; Halbritter et al. 2013. PubMed ID: 23559409; Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant results in a c.1600T>C (p.Cys534Arg) change in an alternate TMEM67 transcript NM_001142301. This variant has been previously reported as a compound heterozygous and homozygous change in patients with nephronophthisis, Joubert syndrome, and Meckel syndrome (PMID: 19574260, 19508969, 21068128, 23559409, 19540516, 20607301, 19466712, 17397051, 21866095). Functional studies demonstrated that the p.Cys615Arg variant prevents localization and disrupts the ability of TMEM67 to regulate Wnt signaling (PMID: 19540516, 26035863). The c.1843T>C (p.Cys615Arg) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. The c.1843T>C (p.Cys615Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.01% (40/282,762). Based on the available evidence, the c.1843T>C (p.Cys615Arg) variant is classified as Pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 615 of the TMEM67 protein (p.Cys615Arg). This variant is present in population databases (rs201893408, gnomAD 0.03%). This missense change has been observed in individual(s) with TMEM67-related ciliopathies (PMID: 19508969, 19540516, 19574260, 20607301, 21068128, 23559409). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1383). 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: 19540516, 26035863). For these reasons, this variant has been classified as Pathogenic. -

Congenital ocular coloboma;C0028738:Nystagmus;C0030305:Pancreatitis;C0031154:Peritonitis;C0036857:Intellectual disability, severe;C0040822:Tremor;C0264172:Barrel-shaped chest;C0557874:Global developmental delay;C1408258:Kidney damage;C1840379:Cerebellar vermis hypoplasia;C1854882:Absent speech;C1860834:Infantile muscular hypotonia;C3665347:Visual impairment;C4025708:Cerebellar malformation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

RHYNS syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 03, 2019

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. -

Nephronophthisis 11

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2009

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2017

- -

Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Oligohydramnios;C0431399:Familial aplasia of the vermis;C3887499:Renal cyst

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jul 01, 2014

- -

Nephronophthisis

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.035

D;D

Polyphen

0.98

D;.

Vest4

0.97

MVP

1.0

MPC

0.58

ClinPred

0.82

GERP RS

5.3

Varity_R

0.90

gMVP

0.90

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