ClinVar Genomic variation as it relates to human health
NM_017849.4(TMEM127):c.464T>A (p.Leu155Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017849.4(TMEM127):c.464T>A (p.Leu155Ter)
Variation ID: 265271 Accession: VCV000265271.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q11.2 2: 96254061 (GRCh38) [ NCBI UCSC ] 2: 96919799 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 10, 2016 May 1, 2024 Jan 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017849.4:c.464T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060319.1:p.Leu155Ter nonsense NM_001193304.3:c.464T>A NP_001180233.1:p.Leu155Ter nonsense NC_000002.12:g.96254061A>T NC_000002.11:g.96919799A>T NG_027695.1:g.16953T>A LRG_528:g.16953T>A LRG_528t1:c.464T>A LRG_528p1:p.Leu155Ter - Protein change
- L155*
- Other names
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- Canonical SPDI
- NC_000002.12:96254060:A:T
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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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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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TMEM127 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
752 | 992 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 5, 2023 | RCV000256121.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 10, 2024 | RCV000558429.8 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 30, 2023 | RCV000564643.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 20, 2023 | RCV001250425.2 |
Submissions - Germline
Classification
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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
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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
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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
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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. |
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Pathogenic
(Feb 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Pheochromocytoma
Affected status: unknown
Allele origin:
germline
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Division of Medical Genetics, University of Washington
Study: CSER_CHARM
Accession: SCV001424779.1 First in ClinVar: Jul 30, 2020 Last updated: Jul 30, 2020 |
Comment:
The c.464T>A variant causes the introduction of a premature termination codon which leads to a truncated protein. The c.464T>A variant has been reported in the … (more)
The c.464T>A variant causes the introduction of a premature termination codon which leads to a truncated protein. The c.464T>A variant has been reported in the literature in individuals with paraganglioma and pheochromocytoma [Patocs 2016]. This variant has an overall allele frequency of 0.00001 in the Genome Aggregation Database (gnomad.broadinstitute.org). Thus, this variant is considered pathogenic. (less)
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Likely pathogenic
(Dec 11, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002527256.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The TMEM127 c.464T>A (p.L155X) variant has been reported in heterozygosity in at least one individual with bilateral pheochromocytoma and intra-abdominal and head/neck paragangliomas (PMID: 26960314). … (more)
The TMEM127 c.464T>A (p.L155X) variant has been reported in heterozygosity in at least one individual with bilateral pheochromocytoma and intra-abdominal and head/neck paragangliomas (PMID: 26960314). It was also reported in two patients with endometrial cancer, melanoma, and/or mesothelioma (PMID: 29625052, 30113886). This nonsense variant creates a premature stop codon at residue 155 of the TMEM127 protein. As this variant is not predicted to cause nonsense-mediated decay, the protein product is expected to be truncated. This variant was observed in 4/282850 chromosomes across all populations in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 265271). Based on the current evidence available, this variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(Sep 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321965.10
First in ClinVar: Oct 10, 2016 Last updated: Sep 14, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation, as the last 84 amino acids are lost, and other loss-of-function variants have been reported downstream in … (more)
Nonsense variant predicted to result in protein truncation, as the last 84 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33051659, 29625052, 30113886, 28384794, 21156949, 26960314, 34308104, 36451132, 37556141) (less)
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Pathogenic
(Aug 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pheochromocytoma
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004206166.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 10, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000637924.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu155*) in the TMEM127 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Leu155*) in the TMEM127 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the TMEM127 protein. This variant is present in population databases (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with pheochromocytoma and paraganglioma (PMID: 26960314; Invitae). ClinVar contains an entry for this variant (Variation ID: 265271). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts a region of the TMEM127 protein in which other variant(s) (p.Gln159*) have been determined to be pathogenic (PMID: 22419703; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jun 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000675310.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.L155* variant (also known as c.464T>A), located in coding exon 3 of the TMEM127 gene, results from a T to A substitution at nucleotide … (more)
The p.L155* variant (also known as c.464T>A), located in coding exon 3 of the TMEM127 gene, results from a T to A substitution at nucleotide position 464. This changes the amino acid from a leucine to a stop codon within coding exon 3. This alteration occurs at the 3' terminus of theTMEM127 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 84 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported as a disease-causing mutation in a 51 year old patient with bilateral pheochromocytoma and intra-abdominal and head/neck paraganglioma (Patócs A et al. Pathol. Oncol. Res., 2016 Oct;22:673-9). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma. | Panou V | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2018 | PMID: 30113886 |
Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
Novel SDHB and TMEM127 Mutations in Patients with Pheochromocytoma/Paraganglioma Syndrome. | Patócs A | Pathology oncology research : POR | 2016 | PMID: 26960314 |
TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. | Abermil N | The Journal of clinical endocrinology and metabolism | 2012 | PMID: 22419703 |
Text-mined citations for rs886039439 ...
HelpRecord last updated May 08, 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.