NM_017849.4(TMEM127):c.409+1G>C AND Hereditary Paraganglioma-Pheochromocytoma Syndromes

Clinical significance:Likely pathogenic (Last evaluated: May 12, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001376818.1

Allele description [Variation Report for NM_017849.4(TMEM127):c.409+1G>C]

NM_017849.4(TMEM127):c.409+1G>C

Gene:
TMEM127:transmembrane protein 127 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q11.2
Genomic location:
Preferred name:
NM_017849.4(TMEM127):c.409+1G>C
HGVS:
  • NC_000002.12:g.96254832C>G
  • NG_027695.1:g.16182G>C
  • NM_001193304.3:c.409+1G>C
  • NM_017849.4:c.409+1G>CMANE SELECT
  • LRG_528:g.16182G>C
  • NC_000002.11:g.96920570C>G
Molecular consequence:
  • NM_001193304.3:c.409+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_017849.4:c.409+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL-PCC)
Synonyms:
Hereditary Paragangliomas and Pheochromocytomas
Identifiers:
MONDO: MONDO:0017366; MedGen: C1708353

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001573990Invitaecriteria provided, single submitter
Likely pathogenic
(May 12, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]
PMID:
9536098
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001573990.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change affects a donor splice site in the last intron (intron 3) of the TMEM127 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with pheochromocytoma and breast cancer (PMID: 21156949). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that disruption of this splice site disrupts mRNA splicing (PMID: 21156949). This variant disrupts transmembrane domains, TM1 and TM2, of the TMEM127 protein, which are required for subcellular localization (PMID: 21156949). While functional studies have not been performed to directly test the effect of this variant on TMEM127 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 14, 2021

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