NM_017849.3(TMEM127):c.410-2A>G AND Hereditary Paraganglioma-Pheochromocytoma Syndromes

Clinical significance:Likely pathogenic (Last evaluated: Feb 27, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000699788.4

Allele description [Variation Report for NM_017849.3(TMEM127):c.410-2A>G]

NM_017849.3(TMEM127):c.410-2A>G

Gene:
TMEM127:transmembrane protein 127 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q11.2
Genomic location:
Preferred name:
NM_017849.3(TMEM127):c.410-2A>G
HGVS:
  • NC_000002.12:g.96254117T>C
  • NG_027695.1:g.16897A>G
  • NM_001193304.3:c.410-2A>G
  • NM_017849.3:c.410-2A>G
  • LRG_528t1:c.410-2A>G
  • LRG_528:g.16897A>G
  • NC_000002.11:g.96919855T>C
Links:
dbSNP: rs121908826
NCBI 1000 Genomes Browser:
rs121908826
Molecular consequence:
  • NM_001193304.3:c.410-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_017849.3:c.410-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000828515Invitaecriteria provided, single submitter
Likely pathogenic
(Feb 27, 2020)
germlineclinical testing

PubMed (7)
[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

Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas.

Eijkelenkamp K, Olderode-Berends MJW, van der Luijt RB, Robledo M, van Dooren M, Feelders RA, de Vries J, Kerstens MN, Links TP, van der Horst-Schrivers ANA.

Clin Genet. 2018 May;93(5):1049-1056. doi: 10.1111/cge.13202. Epub 2018 Mar 23.

PubMed [citation]
PMID:
29282712

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
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000828515.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change affects an acceptor 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). This variant has been observed as homozygous in an individual affected with bilateral pheochromocytoma (PMID: 29282712). ClinVar contains an entry for this variant (Variation ID: 449954). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.410-2A>C, also known as IVS3-2A>C) has been determined to be pathogenic (PMID: 25389632, 20154675, 21156949). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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: Oct 2, 2021

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