NM_001173990.3(TMEM216):c.217C>T (p.Arg73Cys) AND Familial aplasia of the vermis

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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 5, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001053459.5

Allele description

NM_001173990.3(TMEM216):c.217C>T (p.Arg73Cys)

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.217C>T (p.Arg73Cys)

HGVS:

NC_000011.10:g.61393964C>T
NG_032976.1:g.6605C>T
NM_001173990.3:c.217C>TMANE SELECT
NM_001173991.3:c.217C>T
NM_001330285.2:c.34C>T
NM_016499.6:c.34C>T
NP_001167461.1:p.Arg73Cys
NP_001167462.1:p.Arg73Cys
NP_001317214.1:p.Arg12Cys
NP_057583.2:p.Arg12Cys
LRG_698t1:c.217C>T
LRG_698t2:c.217C>T
LRG_698:g.6605C>T
LRG_698p1:p.Arg73Cys
LRG_698p2:p.Arg73Cys
NC_000011.9:g.61161436C>T
NM_001173990.2:c.217C>T
Q9P0N5:p.Arg73Cys

Protein change:

R12C

Links:

UniProtKB: Q9P0N5#VAR_064028; dbSNP: rs779526456

NCBI 1000 Genomes Browser:

rs779526456

Molecular consequence:

NM_001173990.3:c.217C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173991.3:c.217C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330285.2:c.34C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_016499.6:c.34C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial aplasia of the vermis
Synonyms:: CEREBELLOPARENCHYMAL DISORDER IV; Joubert syndrome; Cerebelloparenchymal disorder 4; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018772; MedGen: C0431399; Orphanet: 475; OMIM: PS213300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001217720	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20036350, 20512146, 26092869, 26673778, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001217720

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 5, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

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

Citations

PubMed

Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.

Edvardson S, Shaag A, Zenvirt S, Erlich Y, Hannon GJ, Shanske AL, Gomori JM, Ekstein J, Elpeleg O.

Am J Hum Genet. 2010 Jan;86(1):93-7. doi: 10.1016/j.ajhg.2009.12.007. Epub 2009 Dec 31. Erratum in: Am J Hum Genet. 2010 Feb;86(2):294. Shanske, Alan L [added].

PubMed [citation]

PMID:: 20036350
PMCID:: PMC2801745

Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes.

Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F, Iannicelli M, Travaglini L, Romani S, Illi B, Adams M, Szymanska K, Mazzotta A, Lee JE, Tolentino JC, Swistun D, Salpietro CD, Fede C, Gabriel S, Russ C, Cibulskis K, Sougnez C, et al.

Nat Genet. 2010 Jul;42(7):619-25. doi: 10.1038/ng.594. Epub 2010 May 30.

PubMed [citation]

PMID:: 20512146
PMCID:: PMC2894012

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001217720.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 73 of the TMEM216 protein (p.Arg73Cys). This variant is present in population databases (rs779526456, gnomAD 0.003%). This missense change has been observed in individual(s) with Joubert syndrome or Meckel syndrome (PMID: 20512146, 26092869). ClinVar contains an entry for this variant (Variation ID: 217705). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TMEM216 function (PMID: 20512146). This variant disrupts the p.Arg73 amino acid residue in TMEM216. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20036350, 20512146, 26092869, 26673778). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been 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: Jun 17, 2024

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