11-61393965-G-T

Position:

chr11-61393965-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_001173990.3(TMEM216):c.218G>T(p.Arg73Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TMEM216
NM_001173990.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.70

Variant links:

Genes affected

TMEM216 (HGNC:25018): (transmembrane protein 216) This locus encodes a transmembrane domain-containing protein. Mutations at this locus have been associated with Meckel-Gruber Syndrome Type 2, and Joubert Syndrome 2, also known as Cerebello-oculorenal Syndrome 2. [provided by RefSeq, Aug 2010]

TMEM216 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001173990.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-61393965-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 11-61393965-G-T is Pathogenic according to our data. Variant chr11-61393965-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61393965-G-T is described in Lovd as [Pathogenic]. Variant chr11-61393965-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMEM216	NM_001173990.3 linkuse as main transcript	c.218G>T	p.Arg73Leu	missense_variant	3/5	ENST00000515837.7
TMEM216	NM_001173991.3 linkuse as main transcript	c.218G>T	p.Arg73Leu	missense_variant	3/5
TMEM216	NM_016499.6 linkuse as main transcript	c.35G>T	p.Arg12Leu	missense_variant	3/5
TMEM216	NM_001330285.2 linkuse as main transcript	c.35G>T	p.Arg12Leu	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM216	ENST00000515837.7 linkuse as main transcript	c.218G>T	p.Arg73Leu	missense_variant	3/5	2	NM_001173990.3	P4	Q9P0N5-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000173

AC:

AN:

249228

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000122

AC:

179

AN:

1461606

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00486

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000131

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000271

Hom.:

Bravo

AF:

0.000162

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 2

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 19, 2019	The p.Arg73Leu variant (also called p.Arg12Leu) in TMEM216 is a founder variant in the Ashkenazi Jewish population and has been reported in the homozygous state in at least 20 individuals with Joubert syndrome or Meckel syndrome and segregated with disease in >10 affected individuals from at least 5 families (Edvardson 2010, Schueler 2016, Valente 2010). It has also been identified in 0.338% (35/10352) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported in ClinVar (Variation ID: 197). Computational prediction tools and conservation analyses do not provide evidence for or against pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Valente 2010); however, these types of assays may not accurately represent biological function. Additionally, two variants at the same position (p.Arg73His and p.Arg73Leu) have been identified in individuals with Joubert syndrome, suggesting that a change at this position may not be tolerated. In summary, the p.Arg73Leu variant meets criteria to be classified as pathogenic for autosomal recessive Joubert syndrome. ACMG/AMP criteria applied: PM3_Strong, PP1_Strong, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_001173990.2(TMEM216):c.218G>T(R73L) is classified as pathogenic in the context of Joubert syndrome 2. Sources cited for classification include the following: PMIDs: 20036350, 20512146, and 22282472. Classification of NM_001173990.2(TMEM216):c.218G>T(R73L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2024	Variant summary: TMEM216 c.218G>T (p.Arg73Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251116 control chromosomes The variant has been reported in multiple affected individuals presented with JBTS2 (e.g. Edvardson_2010, Valente_2010). 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_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20036350, 20512146). ClinVar contains an entry for this variant (Variation ID: 197). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2010	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2022	Published functional studies have reported a significant decrease in TMEM216 protein production in cells transfected with R73L compared to the wild type and ciliogenesis disruption in TMEM216-R73L mutated fibroblasts in affected individuals (Lee et al., 2012; Valente et al., 2010); 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: 22282472, 27065010, 27175728, 28125082, 31624327, 31663226, 20512146, 21029074, 20036350, 20301500, 26092869) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 10, 2023	- -

TMEM216-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 21, 2024	The TMEM216 c.218G>T variant is predicted to result in the amino acid substitution p.Arg73Leu. This variant has been reported as pathogenic in multiple patients with Joubert syndrome or Meckel syndrome (described as c.35G>T R12L, Edvardson et al. 2010. PubMed ID: 20036350; Valente et al. 2010. PubMed ID: 20512146; Table S5, Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). This variant has been reported as a founder variant in the Ashkenazi Jewish population, and is reported in 0.34% of alleles in individuals of this descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 14, 2018	The TMEM216 c.218G>T (p.Arg73Leu) missense variant is noted to be a founder variant in the Ashkenazi Jewish population (Parisi et al. 2013). Across a selection of available literature, the p.Arg73Leu variant has been identified in a total of 40 individuals with Joubert syndrome including 39 homozygotes and one compound heterozygote. The variant was also identified in a heterozygous state in 119 unaffected family members (Edvardson et al. 2010; Valente et al. 2010; Bachmann-Gagescu et al. 2015). Additionally the p.Arg73Leu variant was found in a homozygous state in a Turkish family in which Meckel syndrome and Joubert syndrome coexisted within the same sibship (Valente et al. 2010). The p.Arg73Leu variant was reported in 30 of 2766 anonymous Ashkenazi Jewish individuals in a heterozygous state and is reported at a frequency of 0.003381 in the Ashkenazi Jewish population of the Genome Aggregation Database. Lee et al. (2012) reported that fibroblasts from a patient carrying the p.Arg73Leu variant showed failure of ciliogenesis. Based on the collective evidence, the p.Arg73Leu variant is classified as pathogenic for TMEM216-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Meckel syndrome, type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 29, 2016

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.218G>T (p.R73L) alteration is located in exon 3 (coding exon 3) of the TMEM216 gene. This alteration results from a G to T substitution at nucleotide position 218, causing the arginine (R) at amino acid position 73 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.016% (44/280628) total alleles studied. The highest observed frequency was 0.338% (35/10352) of Ashkenazi Jewish alleles. The alteration has been previously reported in multiple individuals with Joubert syndrome from Ashkenazi Jewish families (Edvardson, 2010; Valente, 2010; Bachmann-Gagescu, 2015; Schueler, 2016). Additionally, other variants at this amino acid position have been reported to cause disease (Lee, 2012). This amino acid position is highly conserved in available vertebrate species. Functional analysis on patient fibroblasts demonstrated the p.R73L alteration disrupted ciliogenesis (Lee, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Joubert syndrome 2;C1864148:Meckel syndrome, type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 05, 2022

- -

Familial aplasia of the vermis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 73 of the TMEM216 protein (p.Arg73Leu). This variant is present in population databases (rs201108965, gnomAD 0.4%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 20036350, 26092869). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 20036350, 20512146). ClinVar contains an entry for this variant (Variation ID: 197). 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, 22282472). This variant disrupts the p.Arg73 amino acid residue in TMEM216. Other variant(s) that disrupt this residue have been observed in individuals with TMEM216-related conditions (PMID: 20512146), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;.

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.2

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.2

D;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.010

D;D;D

Vest4

0.98

MVP

0.75

MPC

0.66

ClinPred

0.39

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.93

gMVP

0.93

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