The p.R33* pathogenic mutation (also known as c.97C>T), located in coding exon 3 of the MAX gene, results from a C to T substitution at nucleotide position 97. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been reported in numerous patients with early-onset pheochromocytoma and paraganglioma (Comino-Méndez I et al. Nat. Genet. 2011 Jun;43:663-7; Burnichon N et al. Clin. Cancer Res. 2012 May;18:2828-37). This mutation was also identified in a 25 year-old male with multiple bilateral pheochromoctyomas and bilateral adrenal medullary hyperplasia with all demonstrating negative MAX immunostaining (Romanet P et al. Endocr. Pathol. 2016 Nov [epub ahead of print]). 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.
ClinVar Genomic variation as it relates to human health
NM_002382.5(MAX):c.97C>T (p.Arg33Ter)
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.
(4)
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
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002382.5(MAX):c.97C>T (p.Arg33Ter)
Variation ID: 29788 Accession: VCV000029788.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q23.3 14: 65093782 (GRCh38) [ NCBI UCSC ] 14: 65560500 (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 Aug 22, 2016 May 1, 2024 Sep 17, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002382.5:c.97C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002373.3:p.Arg33Ter nonsense NM_001271068.2:c.70C>T NP_001257997.1:p.Arg24Ter nonsense NM_001271069.2:c.70C>T NP_001257998.1:p.Arg24Ter nonsense NM_001320415.2:c.-178C>T 5 prime UTR NM_001407094.1:c.97C>T NP_001394023.1:p.Arg33Ter nonsense NM_001407095.1:c.70C>T NP_001394024.1:p.Arg24Ter nonsense NM_001407096.1:c.97C>T NP_001394025.1:p.Arg33Ter nonsense NM_001407097.1:c.97C>T NP_001394026.1:p.Arg33Ter nonsense NM_001407099.1:c.70C>T NP_001394028.1:p.Arg24Ter nonsense NM_001407100.1:c.70C>T NP_001394029.1:p.Arg24Ter nonsense NM_001407101.1:c.70C>T NP_001394030.1:p.Arg24Ter nonsense NM_001407102.1:c.70C>T NP_001394031.1:p.Arg24Ter nonsense NM_001407103.1:c.97C>T NP_001394032.1:p.Arg33Ter nonsense NM_001407104.1:c.97C>T NP_001394033.1:p.Arg33Ter nonsense NM_001407105.1:c.-178C>T NM_001407106.1:c.-178C>T NM_001407107.1:c.-178C>T NM_001407108.1:c.70C>T NP_001394037.1:p.Arg24Ter nonsense NM_001407109.1:c.70C>T NP_001394038.1:p.Arg24Ter nonsense NM_001407110.1:c.70C>T NP_001394039.1:p.Arg24Ter nonsense NM_001407111.1:c.-271C>T NM_001407112.1:c.-271C>T NM_001407113.1:c.70C>T NP_001394042.1:p.Arg24Ter nonsense NM_001407114.1:c.120C>T NP_001394043.1:p.Asn40= synonymous NM_145112.3:c.70C>T NP_660087.1:p.Arg24Ter nonsense NM_145113.3:c.97C>T NP_660088.1:p.Arg33Ter nonsense NM_145114.3:c.97C>T NP_660089.1:p.Arg33Ter nonsense NM_197957.4:c.97C>T NP_932061.1:p.Arg33Ter nonsense NR_045122.1:n.366G>A non-coding transcript variant NR_073137.2:n.221C>T NR_073138.2:n.43C>T NR_176275.1:n.239C>T NR_176276.1:n.239C>T NR_176277.1:n.212C>T NR_176278.1:n.70C>T NR_176279.1:n.173C>T NR_176280.1:n.239C>T NR_176281.1:n.239C>T NR_176282.1:n.43C>T NR_176283.1:n.70C>T NC_000014.9:g.65093782G>A NC_000014.8:g.65560500G>A NG_029830.1:g.13728C>T LRG_530:g.13728C>T LRG_530t1:c.97C>T LRG_530p1:p.Arg33Ter - Protein change
- R33*, R24*
- Other names
- -
- Canonical SPDI
- NC_000014.9:65093781:G:A
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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
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| MAX | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
405 | 552 | |
| LOC100506321 | - | - | - | GRCh38 | - | 78 |
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. |
|---|---|---|---|---|
| risk factor (1) |
no assertion criteria provided
|
Jun 19, 2011 | RCV000022655.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 14, 2017 | RCV000562852.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 27, 2022 | RCV000550085.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 17, 2023 | RCV003328552.1 |
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. |
|
|---|---|---|---|---|---|
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Pathogenic
(Feb 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000664488.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.R33* pathogenic mutation (also known as c.97C>T), located in coding exon 3 of the MAX gene, results from a C to T substitution at … (more)
The p.R33* pathogenic mutation (also known as c.97C>T), located in coding exon 3 of the MAX gene, results from a C to T substitution at nucleotide position 97. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been reported in numerous patients with early-onset pheochromocytoma and paraganglioma (Comino-Méndez I et al. Nat. Genet. 2011 Jun;43:663-7; Burnichon N et al. Clin. Cancer Res. 2012 May;18:2828-37). This mutation was also identified in a 25 year-old male with multiple bilateral pheochromoctyomas and bilateral adrenal medullary hyperplasia with all demonstrating negative MAX immunostaining (Romanet P et al. Endocr. Pathol. 2016 Nov [epub ahead of print]). 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
(Sep 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pheochromocytoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004035131.1
First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg33*) in the MAX gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg33*) in the MAX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAX are known to be pathogenic (PMID: 21685915, 26070438). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with sporadic or hereditary pheochromocytoma (PMID: 21685915, 22452945, 27838885). ClinVar contains an entry for this variant (Variation ID: 29788) classified as Pathogenic . For these reasons, this variant has been classified as Pathogenic. (less)
Age: 50-59 years
Sex: female
|
|
|
Pathogenic
(Jan 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary pheochromocytoma-paraganglioma
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000637883.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29788). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29788). This premature translational stop signal has been observed in individual(s) with sporadic or hereditary pheochromocytoma (PMID: 21685915, 22452945, 27838885). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg33*) in the MAX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAX are known to be pathogenic (PMID: 21685915, 26070438). (less)
|
|
|
risk factor
(Jun 19, 2011)
|
no assertion criteria provided
Method: literature only
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PHEOCHROMOCYTOMA, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000043944.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a young man with bilateral nonmalignant pheochromocytoma (171300), Comino-Mendez et al. (2011) identified a heterozygous 97C-T transition in exon 3 of the MAX gene, … (more)
In a young man with bilateral nonmalignant pheochromocytoma (171300), Comino-Mendez et al. (2011) identified a heterozygous 97C-T transition in exon 3 of the MAX gene, resulting in an arg33-to-ter (R33X) substitution. Tumor tissue showed LOH of maternal chromosome 14q. (less)
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg33*) in the MAX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAX are known to be pathogenic (PMID: 21685915, 26070438). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with sporadic or hereditary pheochromocytoma (PMID: 21685915, 22452945, 27838885). ClinVar contains an entry for this variant (Variation ID: 29788) classified as Pathogenic . For these reasons, this variant has been classified as Pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29788). This premature translational stop signal has been observed in individual(s) with sporadic or hereditary pheochromocytoma (PMID: 21685915, 22452945, 27838885). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg33*) in the MAX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAX are known to be pathogenic (PMID: 21685915, 26070438).
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:
The p.R33* pathogenic mutation (also known as c.97C>T), located in coding exon 3 of the MAX gene, results from a C to T substitution at nucleotide position 97. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been reported in numerous patients with early-onset pheochromocytoma and paraganglioma (Comino-Méndez I et al. Nat. Genet. 2011 Jun;43:663-7; Burnichon N et al. Clin. Cancer Res. 2012 May;18:2828-37). This mutation was also identified in a 25 year-old male with multiple bilateral pheochromoctyomas and bilateral adrenal medullary hyperplasia with all demonstrating negative MAX immunostaining (Romanet P et al. Endocr. Pathol. 2016 Nov [epub ahead of print]). 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:
This sequence change creates a premature translational stop signal (p.Arg33*) in the MAX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAX are known to be pathogenic (PMID: 21685915, 26070438). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with sporadic or hereditary pheochromocytoma (PMID: 21685915, 22452945, 27838885). ClinVar contains an entry for this variant (Variation ID: 29788) classified as Pathogenic . For these reasons, this variant has been classified as Pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29788). This premature translational stop signal has been observed in individual(s) with sporadic or hereditary pheochromocytoma (PMID: 21685915, 22452945, 27838885). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg33*) in the MAX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAX are known to be pathogenic (PMID: 21685915, 26070438).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation. | Romanet P | Endocrine pathology | 2017 | PMID: 27838885 |
| Functional and in silico assessment of MAX variants of unknown significance. | Comino-Méndez I | Journal of molecular medicine (Berlin, Germany) | 2015 | PMID: 26070438 |
| MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. | Burnichon N | Clinical cancer research : an official journal of the American Association for Cancer Research | 2012 | PMID: 22452945 |
| Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. | Comino-Méndez I | Nature genetics | 2011 | PMID: 21685915 |
Text-mined citations for rs387906651 ...
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.