NM_003000.2(SDHB):c.3G>A (p.Met1Ile) AND Paragangliomas 4

Clinical significance:Likely pathogenic (Last evaluated: Mar 27, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000550393.1

Allele description [Variation Report for NM_003000.2(SDHB):c.3G>A (p.Met1Ile)]

NM_003000.2(SDHB):c.3G>A (p.Met1Ile)

Gene:
SDHB:succinate dehydrogenase complex iron sulfur subunit B [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p36.13
Genomic location:
Preferred name:
NM_003000.2(SDHB):c.3G>A (p.Met1Ile)
HGVS:
  • NC_000001.11:g.17054017C>T
  • NG_012340.1:g.5154G>A
  • NM_003000.2:c.3G>A
  • NP_002991.2:p.Met1Ile
  • LRG_316t1:c.3G>A
  • LRG_316:g.5154G>A
  • LRG_316p1:p.Met1Ile
  • NC_000001.10:g.17380512C>T
Protein change:
M1I
Links:
dbSNP: rs1131691061
NCBI 1000 Genomes Browser:
rs1131691061
Molecular consequence:
  • NM_003000.2:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Paragangliomas 4 (PGL4)
Synonyms:
CAROTID BODY TUMORS AND MULTIPLE EXTRAADRENAL PHEOCHROMOCYTOMAS; Pheochromocytoma, extraadrenal and cervical paraganglioma; Paragangliomas, hereditary extraadrenal; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007273; MedGen: C1861848; Orphanet: 29072; OMIM: 115310

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000644758Invitaecriteria provided, single submitter
Likely pathogenic
(Mar 27, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000644758.1

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

Description

This sequence change affects the initiator methionine of the SDHB mRNA. The next in-frame methionine is located at codon 58. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with paragangliomas, pheochromocytomas and renal cell carcinomas (PMID: 19351833, 23407919, 24096523, 27279923, 22241717). This variant is expected to result in an absent or disrupted protein product. If translation initiation is rescued by the downstream methionine at codon 58, this would result in loss of the mitochondrial targeting sequence (residues 1-28), and partially affect Fe-S binding domain (residues 40-133) of the SDHB protein (PMID: 23083876). A missense change (p.Arg46Gln) within the N-terminal region has been determined to be pathogenic (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968), suggesting that this variant is expected to disrupt SDHB protein function. In summary, this variant is a rare initiator codon variant that has been observed in affected individuals, and is expected to disrupt an important protein domain. This evidence indicates that the variant is pathogenic, but additional data is 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 7, 2021

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