A published H96R variant that is likely pathogenic has been identified in the TMEM138 gene. The H96R variant has been reported previous in association with Joubert syndrome and related disorders (JSRD) (Lee et al., 2012; Szymanska et al., 2012). Funcational studies suggest that the H96R variant results in an unstable protein (Lee et al., 2012). The H96R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the H96R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
ClinVar Genomic variation as it relates to human health
NM_016464.5(TMEM138):c.287A>G (p.His96Arg)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(5)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_016464.5(TMEM138):c.287A>G (p.His96Arg)
Variation ID: 31188 Accession: VCV000031188.7
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q12.2 11: 61366203 (GRCh38) [ NCBI UCSC ] 11: 61133675 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 Feb 14, 2024 Jan 4, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_016464.5:c.287A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057548.1:p.His96Arg missense NM_001330281.2:c.113A>G NP_001317210.1:p.His38Arg missense NR_028473.2:n.356A>G non-coding transcript variant NC_000011.10:g.61366203A>G NC_000011.9:g.61133675A>G NG_032581.1:g.9203A>G Q9NPI0:p.His96Arg - Protein change
- H96R, H38R
- Other names
- -
- Canonical SPDI
- NC_000011.10:61366202:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Unknown function
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TMEM138 | - | - |
GRCh38 GRCh37 |
157 | 177 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 4, 2024 | RCV000024187.10 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 21, 2017 | RCV000423402.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jul 21, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000521218.4
First in ClinVar: Mar 08, 2017 Last updated: Dec 19, 2017 |
Comment:
A published H96R variant that is likely pathogenic has been identified in the TMEM138 gene. The H96R variant has been reported previous in association with … (more)
A published H96R variant that is likely pathogenic has been identified in the TMEM138 gene. The H96R variant has been reported previous in association with Joubert syndrome and related disorders (JSRD) (Lee et al., 2012; Szymanska et al., 2012). Funcational studies suggest that the H96R variant results in an unstable protein (Lee et al., 2012). The H96R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the H96R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. (less)
|
|
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Pathogenic
(Jan 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Joubert syndrome 16
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002228732.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 96 of the TMEM138 protein (p.His96Arg). … (more)
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 96 of the TMEM138 protein (p.His96Arg). This variant is present in population databases (rs387907132, gnomAD 0.02%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 22282472). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31188). 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 TMEM138 function (PMID: 22282472). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Likely pathogenic
(Sep 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Joubert syndrome 16
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001433669.1
First in ClinVar: Oct 01, 2020 Last updated: Oct 01, 2020 |
Comment:
A homozygous missense variation in exon 3 of the TMEM138 gene that results in the amino acid substitution of Arginine for Histidine at codon 96 … (more)
A homozygous missense variation in exon 3 of the TMEM138 gene that results in the amino acid substitution of Arginine for Histidine at codon 96 was detected. The observed variant c.287A>G (p.His96Arg) lies in the transmembrane protein 138 domain of the TMEM138 protein and has previously been reported in patients affected with Joubert syndrome (Lee et al. 2012). The variant is classified as likely pathogenic in ClinVar database. The variant has not been reported in the 1000 genomes and has a minor allele frequency of 0.002% in the gnomAD database. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. (less)
Clinical Features:
Dandy-Walker malformation (present)
Ethnicity/Population group: Gujarati/Hindu
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
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Likely pathogenic
(Mar 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Joubert syndrome 16
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004238763.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Feb 24, 2012)
|
no assertion criteria provided
Method: literature only
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JOUBERT SYNDROME 16
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000045478.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 19, 2018 |
Comment on evidence:
In 2 Arab sibs, born of consanguineous parents, with Joubert syndrome (JBTS16; 614465), Lee et al. (2012) identified a homozygous 287A-G transition in the TMEM138 … (more)
In 2 Arab sibs, born of consanguineous parents, with Joubert syndrome (JBTS16; 614465), Lee et al. (2012) identified a homozygous 287A-G transition in the TMEM138 gene, resulting in a his96-to-arg (H96R) substitution in a highly conserved residue. A 17-year-old boy had the molar tooth sign and a Dandy-Walker malformation, oculomotor apraxia, and nephronophthisis. An affected fetus had an encephalocele and was diagnosed with Meckel syndrome. In vitro functional expression studies showed that the mutant H96R protein was expressed at about 40% of control levels, suggesting a loss of function as the disease mechanism. (less)
|
Comment:
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 96 of the TMEM138 protein (p.His96Arg). This variant is present in population databases (rs387907132, gnomAD 0.02%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 22282472). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31188). 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 TMEM138 function (PMID: 22282472). For these reasons, this variant has been classified as Pathogenic.
Comment:
A homozygous missense variation in exon 3 of the TMEM138 gene that results in the amino acid substitution of Arginine for Histidine at codon 96 was detected. The observed variant c.287A>G (p.His96Arg) lies in the transmembrane protein 138 domain of the TMEM138 protein and has previously been reported in patients affected with Joubert syndrome (Lee et al. 2012). The variant is classified as likely pathogenic in ClinVar database. The variant has not been reported in the 1000 genomes and has a minor allele frequency of 0.002% in the gnomAD database. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
Unknown function
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001433669.1
|
|
Comment:
A published H96R variant that is likely pathogenic has been identified in the TMEM138 gene. The H96R variant has been reported previous in association with Joubert syndrome and related disorders (JSRD) (Lee et al., 2012; Szymanska et al., 2012). Funcational studies suggest that the H96R variant results in an unstable protein (Lee et al., 2012). The H96R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the H96R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 96 of the TMEM138 protein (p.His96Arg). This variant is present in population databases (rs387907132, gnomAD 0.02%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 22282472). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31188). 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 TMEM138 function (PMID: 22282472). For these reasons, this variant has been classified as Pathogenic.
Comment:
A homozygous missense variation in exon 3 of the TMEM138 gene that results in the amino acid substitution of Arginine for Histidine at codon 96 was detected. The observed variant c.287A>G (p.His96Arg) lies in the transmembrane protein 138 domain of the TMEM138 protein and has previously been reported in patients affected with Joubert syndrome (Lee et al. 2012). The variant is classified as likely pathogenic in ClinVar database. The variant has not been reported in the 1000 genomes and has a minor allele frequency of 0.002% in the gnomAD database. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Evolutionarily assembled cis-regulatory module at a human ciliopathy locus. | Lee JH | Science (New York, N.Y.) | 2012 | PMID: 22282472 |
Text-mined citations for rs387907132 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.