VCV000397511.23 - ClinVar

NM_017849.4(TMEM127):c.117_120del (p.Ile41fs)

Germline

Classification

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.

(10)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_017849.4(TMEM127):c.117_120del (p.Ile41fs)

Variation ID: 397511 Accession: VCV000397511.23

Type and length

Deletion, 4 bp

Location

Cytogenetic: 2q11.2 2: 96265262-96265265 (GRCh38) [ NCBI UCSC ] 2: 96931000-96931003 (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	Apr 24, 2014	Oct 8, 2024	May 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

I41fs

Other names

Canonical SPDI

NC_000002.12:96265261:AGACAG:AG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA269736 dbSNP: rs121908816 VarSome

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
Gene	OMIM	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.
TMEM127		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	776	1022
LOC129934333	-	-	-	GRCh38	-	200

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.
Pheochromocytoma	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 27, 2024	RCV000449515.7
Hereditary pheochromocytoma-paraganglioma	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 17, 2024	RCV000556401.11
not provided	Pathogenic (1)	criteria provided, single submitter	May 9, 2024	RCV000485576.7
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 19, 2024	RCV000574362.5
TMEM127-related disorder	Likely pathogenic (1)	no assertion criteria provided	Aug 23, 2024	RCV004755920.1

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.
Pathogenic (Jul 12, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pheochromocytoma Affected status: yes Allele origin: germline	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
Pathogenic (Dec 09, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002527238.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The TMEM127 c.117_120delGTCT (p.I41RfsX39) variant has been reported in at least 16 individuals with pheochromocytoma (PMID:22541004, 21156949, 33051659, doi: 10.1210/jendso/bvab048.2058). It is also known as … (more) The TMEM127 c.117_120delGTCT (p.I41RfsX39) variant has been reported in at least 16 individuals with pheochromocytoma (PMID:22541004, 21156949, 33051659, doi: 10.1210/jendso/bvab048.2058). It is also known as c.116_119delTGTC in the literature. This variant causes a frameshift at amino acid 41 that results in premature termination 39 amino acids downstream. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). Loss-of-function variants in TMEM127 are known to be pathogenic (PMID: 21156949). It was observed in 1/20188 chromosomes of the African/African American subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654), and has been reported in ClinVar (Variation ID 397511). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (3) PubMed: 22541004‚ 21156949‚ 33051659
Pathogenic (Aug 19, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary pheochromocytoma-paraganglioma Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002572184.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (4) PubMed: 33051659‚ 21156949‚ 26269449‚ 22541004 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)
Pathogenic (Jan 17, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary pheochromocytoma-paraganglioma Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000637904.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 28492532‚ 20154675‚ 21156949‚ 22541004 Comment: This sequence change creates a premature translational stop signal (p.Ile41Argfs39) 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.Ile41Argfs39) 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)
Pathogenic (Jan 19, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000675298.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 21156949‚ 22541004 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 alteration has been identified in individuals diagnosed with paragangliomas and/or pheochromocytomas (Takeichi N et al. Clin. Endocrinol. (Oxf), 2012 Nov;77:707-14; Yao L et al. JAMA, 2010 Dec;304:2611-9). Of note, this alteration is also known as c.116_119delTGTC in published literature. 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)
Pathogenic (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pheochromocytoma Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004041267.2 First in ClinVar: Oct 07, 2023 Last updated: Jun 17, 2024
Pathogenic (May 09, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000567003.10 First in ClinVar: Apr 27, 2017 Last updated: Jul 23, 2024	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 … (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: 37529773, 26269449, 28973655, 21156949, 37358160, 34906458, 22541004, 33051659) (less)
likely pathogenic - adrenal pheochromocytoma (-)	no assertion criteria provided Method: not provided	Pheochromocytoma Affected status: not provided Allele origin: germline	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.
Likely pathogenic (Aug 23, 2024)	no assertion criteria provided Method: clinical testing	TMEM127-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005347869.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The TMEM127 c.117_120delGTCT variant is predicted to result in a frameshift and premature protein termination (p.Ile41Argfs39). In the literature, this variant is also reported as … (more) The TMEM127 c.117_120delGTCT variant is predicted to result in a frameshift and premature protein termination (p.Ile41Argfs39). In the literature, this variant is also reported as c.116_119delGTCT and c.115_118delCTGT. This variant was reported in multiple individuals with pheochromocytoma (Yao et al. 2010. PubMed ID: 21156949; Lima et al. 2023. PubMed ID: 37529773; Table S1, Currás-Freixes et al. 2015. PubMed ID: 26269449). Of note, one of those individuals also had a TP53 variant and breast and pancreatic cancers (Lima et al 2023. PubMed ID: 37529773). This variant is reported in 0.0050% of alleles in individuals of African descent in gnomAD. Frameshift variants in TMEM127 are expected to be pathogenic. This variant is interpreted as likely pathogenic. (less)
not provided (-)	no classification provided Method: phenotyping only	Pheochromocytoma Affected status: unknown Allele origin: unknown	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

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 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.

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 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.

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 120, causing a translational frameshift with a predicted alternate stop codon (p.I41Rfs*39). This alteration has been identified in individuals diagnosed with paragangliomas and/or pheochromocytomas (Takeichi N et al. Clin. Endocrinol. (Oxf), 2012 Nov;77:707-14; Yao L et al. JAMA, 2010 Dec;304:2611-9). Of note, this alteration is also known as c.116_119delTGTC in published literature. 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.

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 observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37529773, 26269449, 28973655, 21156949, 37358160, 34906458, 22541004, 33051659)

Comment:

The TMEM127 c.117_120delGTCT variant is predicted to result in a frameshift and premature protein termination (p.Ile41Argfs*39). In the literature, this variant is also reported as c.116_119delGTCT and c.115_118delCTGT. This variant was reported in multiple individuals with pheochromocytoma (Yao et al. 2010. PubMed ID: 21156949; Lima et al. 2023. PubMed ID: 37529773; Table S1, Currás-Freixes et al. 2015. PubMed ID: 26269449). Of note, one of those individuals also had a TP53 variant and breast and pancreatic cancers (Lima et al 2023. PubMed ID: 37529773). This variant is reported in 0.0050% of alleles in individuals of African descent in gnomAD. Frameshift variants in TMEM127 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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 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.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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 ...

These 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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_017849.4(TMEM127):c.117_120del (p.Ile41fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908816 ...