ClinVar Genomic variation as it relates to human health
NM_017849.4(TMEM127):c.117_120del (p.Ile41fs)
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.117_120del (p.Ile41fs)
Variation ID: 397511 Accession: VCV000397511.19
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 2q11.2 2: 96265262-96265265 (GRCh38) [ NCBI UCSC ] 2: 96931000-96931003 (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 Apr 24, 2014 Feb 14, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017849.4:c.117_120del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060319.1:p.Ile41fs frameshift NM_001193304.3:c.117_120del NP_001180233.1:p.Ile41fs frameshift NM_017849.3:c.117_120delGTCT NC_000002.12:g.96265264_96265267del NC_000002.11:g.96931002_96931005del NG_027695.1:g.5749_5752del LRG_528:g.5749_5752del - Protein change
- I41fs
- Other names
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- Canonical SPDI
- NC_000002.12:96265261:AGACAG:AG
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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.
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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 |
720 | 955 | |
LOC129934333 | - | - | - | GRCh38 | - | 191 |
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
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
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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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2023 | RCV000449515.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV000556401.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 9, 2021 | RCV000574362.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 27, 2023 | RCV000485576.6 |
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
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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
(Jul 12, 2016)
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criteria provided, single submitter
Method: clinical testing
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Pheochromocytoma
Affected status: yes
Allele origin:
germline
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Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV000537698.1
First in ClinVar: Mar 27, 2017 Last updated: Mar 27, 2017 |
Age: 40-50 years
Sex: female
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Pathogenic
(Oct 27, 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: SCV000567003.9
First in ClinVar: Apr 27, 2017 Last updated: Nov 25, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22541004, 26269449, 28973655, 21156949) (less)
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Pathogenic
(Jan 17, 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: SCV000637904.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ile41Argfs*39) in the TMEM127 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ile41Argfs*39) in the TMEM127 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM127 are known to be pathogenic (PMID: 20154675, 21156949). This variant is present in population databases (rs121908816, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with adrenal pheochromocytoma (PMID: 21156949, 22541004). This variant is also known as c.116_119delTGTC. ClinVar contains an entry for this variant (Variation ID: 397511). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 09, 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: SCV002527238.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Pathogenic
(Aug 19, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572184.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: TMEM127 c.117_120delGTCT (p.Ile41ArgfsX39) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: TMEM127 c.117_120delGTCT (p.Ile41ArgfsX39) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.5e-05 in 200316 control chromosomes (gnomAD). c.117_120delGTCT has been reported in the literature in multiple individuals with pheochromocytomas (e.g.Yao_2010, Takeichi_2012, Curras_Freixes_2015, Armaiz-Pena_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 04, 2020)
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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: SCV000675298.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
The c.117_120delGTCT pathogenic mutation, located in coding exon 1 of the TMEM127 gene, results from a deletion of 4 nucleotides at nucleotide positions 117 to … (more)
The c.117_120delGTCT pathogenic mutation, located in coding exon 1 of the TMEM127 gene, results from a deletion of 4 nucleotides at nucleotide positions 117 to 120, causing a translational frameshift with a predicted alternate stop codon (p.I41Rfs*39). This mutation (designated as c.116_119delTGTC) has been identified in individuals diagnosed with paragangliomas and pheochromocytomas (Takeichi N et al. Clin. Endocrinol. (Oxf), 2012 Nov;77:707-14; Yao L et al. JAMA, 2010 Dec;304:2611-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 26, 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: SCV004041267.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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likely pathogenic - adrenal pheochromocytoma
(-)
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no assertion criteria provided
Method: not provided
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Pheochromocytoma
Affected status: not provided
Allele origin:
germline
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Familial Cancer Clinic, Veneto Institute of Oncology
Accession: SCV000148714.1
First in ClinVar: Apr 24, 2014 Last updated: Apr 24, 2014 |
Comment:
Converted during submission to Likely pathogenic.
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not provided
(-)
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no classification provided
Method: phenotyping only
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Pheochromocytoma
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749822.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 10-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 10-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Hypermetropia (present) , Abnormality of vision (present) , Myopia (present) , Abnormal retinal morphology (present) , Abnormality of the nose (present) , Anxiety (present) , … (more)
Hypermetropia (present) , Abnormality of vision (present) , Myopia (present) , Abnormal retinal morphology (present) , Abnormality of the nose (present) , Anxiety (present) , Bipolar affective disorder (present) , Depression (present) (less)
Indication for testing: Presymptomatic
Age: 50-59 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-10-11
Testing laboratory interpretation: Pathogenic
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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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Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update. | Armaiz-Pena G | The Journal of clinical endocrinology and metabolism | 2021 | PMID: 33051659 |
Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. | Currás-Freixes M | Journal of medical genetics | 2015 | PMID: 26269449 |
Identical germline mutations in the TMEM127 gene in two unrelated Japanese patients with bilateral pheochromocytoma. | Takeichi N | Clinical endocrinology | 2012 | PMID: 22541004 |
Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. | Yao L | JAMA | 2010 | PMID: 21156949 |
Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. | Qin Y | Nature genetics | 2010 | PMID: 20154675 |
Text-mined citations for rs121908816 ...
HelpRecord last updated Feb 20, 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.