8-93795970-T-C

Variant names:

• chr8-93795970-T-C
• rs201893408
• NM_153704.6:c.1843T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM5 PP3_Moderate PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C615Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 7.25
• Publications: 24 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-93795971-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1349411.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 1383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153704.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	NM_153704.6	MANE Select	c.1843T>C	p.Cys615Arg	missense	Exon 18 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.1600T>C	p.Cys534Arg	missense	Exon 19 of 29	NP_001135773.1
	TMEM67	NR_024522.2		n.1864T>C		non_coding_transcript_exon	Exon 18 of 29

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.1843T>C	p.Cys615Arg	missense	Exon 18 of 28	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.1843T>C	p.Cys615Arg	missense	Exon 18 of 27	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.981T>C		non_coding_transcript_exon	Exon 9 of 17

Frequencies

GnomAD3 genomes AF: 0.0000919 AC: 14 AN: 152276 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000147 AC: 37 AN: 251362 AF XY: 0.000103

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 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.: 0 Cov.: 31 AF XY: 0.0000922 AC XY: 67 AN XY: 726766

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1111114

Other (OTH) AF: 0.0000663 AC: 4 AN: 60348

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74402

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000187 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Jul 10, 2025

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Joubert syndrome 6 Pathogenic:3

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Feb 10, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

TMEM67-related disorder Pathogenic:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oligohydramnios;C0431399:Joubert syndrome;C3887499:Renal cyst Pathogenic:1

Jul 01, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Pathogenic:1

Aug 08, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joubert syndrome and related disorders Pathogenic:1

Jul 14, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TMEM67 c.1843T>C (p.Cys615Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.00015 in 251362 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TMEM67 causing Joubert Syndrome And Related Disorders (0.00015 vs 0.0018), allowing no conclusion about variant significance. c.1843T>C has been observed in multiple individuals affected with Nephronophthisis (example: Kong_2022). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 36090483). ClinVar contains an entry for this variant (Variation ID: 1383). Based on the evidence outlined above, the variant was classified as pathogenic.

RHYNS syndrome Pathogenic:1

Oct 03, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nephronophthisis 11 Pathogenic:1

Oct 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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:Floppy infant;C3665347:Visual impairment;C4025708:Cerebellar malformation Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joubert syndrome 6;C1865794:RHYNS syndrome;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 Pathogenic:1

Feb 20, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Meckel-Gruber syndrome;C0431399:Joubert syndrome Pathogenic:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Nephronophthisis Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.035	D
Polyphen		0.98	D
Vest4		0.97
MVP		1.0
MPC		0.58
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.90
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs201893408; hg19: chr8-94808198;