NM_001173990.3(TMEM216):c.218G>T (p.Arg73Leu) AND Joubert syndrome 2

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Feb 29, 2016
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:: RCV000000220.3

Allele description

NM_001173990.3(TMEM216):c.218G>T (p.Arg73Leu)

Gene:

TMEM216:transmembrane protein 216 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q12.2

Genomic location:

Preferred name:

NM_001173990.3(TMEM216):c.218G>T (p.Arg73Leu)

HGVS:

NC_000011.10:g.61393965G>T
NG_032976.1:g.6606G>T
NM_001173990.3:c.218G>T
NM_001173991.2:c.218G>T
NM_001330285.1:c.35G>T
NM_016499.5:c.35G>T
NP_001167461.1:p.Arg73Leu
NP_001167462.1:p.Arg73Leu
NP_001317214.1:p.Arg12Leu
NP_057583.2:p.Arg12Leu
NC_000011.9:g.61161437G>T
NM_001173990.2:c.218G>T
Q9P0N5:p.Arg73Leu

Nucleotide change:

c.218G>T

Protein change:

R12L; ARG73LEU

Links:

UniProtKB: Q9P0N5#VAR_063388; OMIM: 613277.0001; dbSNP: rs201108965

NCBI 1000 Genomes Browser:

rs201108965

Molecular consequence:

NM_001173990.3:c.218G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173991.2:c.218G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330285.1:c.35G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_016499.5:c.35G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Joubert syndrome 2 (JBTS2)
Identifiers:: MedGen: C1842577; Orphanet: 2318; OMIM: 608091

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020363	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 2010)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 20036350, 20512146
SCV000058601	GeneReviews	no assertion criteria provided	pathologic (Mar 29, 2012)	not provided	curation
SCV000256482	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 (Submitter's publication)	Pathogenic (Feb 23, 2015)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV000487404	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Feb 29, 2016)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22282472, 20512146, 20036350 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000697775	Integrated Genetics/Laboratory Corporation of America	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 22, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20512146, 20036350 LabCorp Variant Classification Summary - May 2015.docx Citation Link

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Summary from all submissions

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

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

Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.

Lee JH, Silhavy JL, Lee JE, Al-Gazali L, Thomas S, Davis EE, Bielas SL, Hill KJ, Iannicelli M, Brancati F, Gabriel SB, Russ C, Logan CV, Sharif SM, Bennett CP, Abe M, Hildebrandt F, Diplas BH, Attié-Bitach T, Katsanis N, Rajab A, Koul R, et al.

Science. 2012 Feb 24;335(6071):966-9. doi: 10.1126/science.1213506. Epub 2012 Jan 26.

PubMed [citation]

PMID:: 22282472
PMCID:: PMC3671610

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000020363.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 13 affected members of 8 Ashkenazi Jewish families with Joubert syndrome-2 (JBTS2; 608091), Edvardson et al. (2010) identified a homozygous 218G-T transversion in exon 4 of the TMEM216 gene, resulting in an arg73-to-leu (R73L) substitution in a conserved residue. This mutation was designated ARG12LEU by Edvardson et al. (2010). All of the parents and several unaffected relatives were heterozygous carriers of the mutation, indicating a carrier rate of 1 in 92 in this ethnic group. The phenotype was characterized by neonatal hypotonia, mental retardation, and posterior fossa abnormalities.

In affected members of 12 families with JBTS2, Valente et al. (2010) identified a homozygous 218G-T transversion in exon 4 of the TMEM216 gene, resulting in an arg73-to-leu (R73L) substitution. Two of the families were from Sicily, and 10 were of Ashkenazi Jewish origin. Haplotype analysis indicated a common founder that dated back at least 20 generations. The carrier frequency in the Ashkenazi Jewish population was determined to be 1 in 100. Two individuals with Joubert syndrome and the R73L mutation who had polydactyly also demonstrated tongue tumors or multiple oral frenula, respectively, reminiscent of orofaciodigital syndrome type VI (OFD6; 277170).

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

From GeneReviews, SCV000058601.1

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

Description

Converted during submission to Pathogenic.

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

From UW Hindbrain Malformation Research Program,University of Washington, SCV000256482.1

#	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 Counsyl, SCV000487404.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

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

From Integrated Genetics/Laboratory Corporation of America, SCV000697775.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: The c.218G>T in TMEM216 gene is a missense variant that involves a non-conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is present in the broad control population dataset of ExAC at a low frequency, exclusively in European cohort (0.024%), which does not exceed the maximum frequency for a pathogenic variant in TMEM216 gene (0.39%), suggesting this variant is not a common polymorphism. The variant has been reported in multiple affected individuals presented with JBTS2. This variant is considered to be a founder mutation in individuals of Ashkenazi Jewish descent. The carrier frequency in the Ashkenazi population was reported to be about 1:100 (Valente et al., 2010). The variant of interest has been reported as Pathogenic by several reputable databases. Taking together, the variant was classified as Pathogenic.

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

Last Updated: Mar 4, 2020

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