NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser) AND Joubert syndrome 6

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 3, 2018
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000201726.5

Allele description [Variation Report for NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser)]

NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser)

Gene:

TMEM67:transmembrane protein 67 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q22.1

Genomic location:

Preferred name:

NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser)

HGVS:

NC_000008.11:g.93780603A>G
NG_009190.1:g.30760A>G
NM_001142301.1:c.482A>G
NM_153704.6:c.725A>GMANE SELECT
NP_001135773.1:p.Asn161Ser
NP_714915.3:p.Asn242Ser
NP_714915.3:p.Asn242Ser
LRG_688t1:c.725A>G
LRG_688t2:c.482A>G
LRG_688:g.30760A>G
LRG_688p1:p.Asn242Ser
LRG_688p2:p.Asn161Ser
NC_000008.10:g.94792831A>G
NM_153704.5:c.725A>G
NR_024522.2:n.746A>G
p.Asn242Ser

Protein change:

N161S

Links:

dbSNP: rs775883520

NCBI 1000 Genomes Browser:

rs775883520

Molecular consequence:

NM_001142301.1:c.482A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_153704.6:c.725A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_024522.2:n.746A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Joubert syndrome 6 (JBTS6)
Identifiers:: MONDO: MONDO:0012539; MedGen: C1853153; Orphanet: 475; OMIM: 610688

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000256502	UW Hindbrain Malformation Research Program, University of Washington See additional submitters University of Washington Center for Mendelian Genomics, University of Washington	criteria provided, single submitter (Bachmann-Gagescu et al. (J Med Genet. 2015))	Pathogenic (Feb 23, 2015)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001164356	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2018)	germline	research	PubMed (4) [See all records that cite these PMIDs] 28719906, 19574260, 23559409, 25741868
SCV004232727	Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research	no assertion criteria provided	Pathogenic	biparental	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000256502

UW Hindbrain Malformation Research Program, University of Washington

See additional submitters

criteria provided, single submitter

(Bachmann-Gagescu et al. (J Med Genet. 2015))

Pathogenic
(Feb 23, 2015)

unknown

research

PubMed (1)
[See all records that cite this PMID]

SCV001164356

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 3, 2018)

germline

research

PubMed (4)
[See all records that cite these PMIDs]

SCV004232727

Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research

no assertion criteria provided

Pathogenic

biparental

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	biparental	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.

Bachmann-Gagescu R, Dempsey JC, Phelps IG, O'Roak BJ, Knutzen DM, Rue TC, Ishak GE, Isabella CR, Gorden N, Adkins J, Boyle EA, de Lacy N, O'Day D, Alswaid A, Ramadevi A R, Lingappa L, Lourenço C, Martorell L, Garcia-Cazorla À, Ozyürek H, Haliloğlu G, Tuysuz B, et al.

J Med Genet. 2015 Aug;52(8):514-22. doi: 10.1136/jmedgenet-2015-103087. Epub 2015 Jun 19.

PubMed [citation]

PMID:: 26092869
PMCID:: PMC5082428

A Common Ancestral Asn242Ser Mutation in TMEM67 Identified in Multiple Iranian Families with Joubert Syndrome.

Dehghani M, Mojarad M, Ghayoor Karimiani E, Vahidi Mehrjardi MY, Sahebalzamani A, Ashrafzadeh F, Beiraghi Toosi M, Eslahi A, Ahangari N, Yassini SM, Hassanbeigi A, Rasti A, Kalantar SM, Maroofian R.

Public Health Genomics. 2017;20(3):188-193. doi: 10.1159/000477560. Epub 2017 Jul 19.

PubMed [citation]

PMID:: 28719906

See all PubMed Citations (5)

Details of each submission

From UW Hindbrain Malformation Research Program, University of Washington, SCV000256502.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164356.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (4)

Description

The homozygous p.Asn242Ser variant in TMEM67 was identified by our study in one individual with Joubert syndrome. The p.Asn242Ser variant in TMEM67 was reported in 23 individuals (including 22 Iranians) with Joubert syndrome, segregated with disease in 22 affected relatives from 9 families (PMID: 28719906, 19574260), and has been identified in 0.002978% (1/33580) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775883520). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency and its prevalence in Iranian families with a shared haplotype suggests this is a founder variant (PMID: 28719906). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant was also reported likely pathogenic in ClinVar prior to the publication of a paper about 22 Iranians from 9 families with this variant and Joubert syndrome (Variation ID: 216826). Two additional variants at the the same position, p.Asn242Thr and p.Asn242Lys, have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 23559409, 19574260). Position 242 in the TMEM67 protein has also been reported as a glycosylation site for GlcNAc, providing additional support that a change in this position may not be tolerated (Entry: Q5HYA8) In summary, this variant meets criteria to be classified as pathogenic for Joubert syndrome in an autosomal recessive manner based on the predicted impact of a change at position 242 in TMEM67 and cosegregation with Joubertssyndrome in multiple Iranian families. ACMG/AMP Criteria applied: PM2, PP3, PM5, PM1_Supporting, PP1_Strong (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, SCV004232727.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

A generation of sequencing tests were performed on the foetus's parents and the prior witness: the father carried c. 475 T >C;Het, mother carrying c. 725A> G;Het, daughter carrying c. 475 T >C; c. 725A> G double heterozygous, the fetus and the first witness inherited the genetic mutations of both parents

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	biparental	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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