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NM_148919.4(PSMB8):c.224C>T (p.Thr75Met) AND Proteosome-associated autoinflammatory syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 19, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003596608.2

Allele description [Variation Report for NM_148919.4(PSMB8):c.224C>T (p.Thr75Met)]

NM_148919.4(PSMB8):c.224C>T (p.Thr75Met)

Gene:
PSMB8:proteasome 20S subunit beta 8 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6p21.32
Genomic location:
Preferred name:
NM_148919.4(PSMB8):c.224C>T (p.Thr75Met)
HGVS:
  • NC_000006.12:g.32843013G>A
  • NG_009793.3:g.758C>T
  • NG_028165.1:g.6923C>T
  • NM_004159.5:c.212C>T
  • NM_148919.4:c.224C>TMANE SELECT
  • NP_004150.1:p.Thr71Met
  • NP_683720.2:p.Thr75Met
  • LRG_1328t1:c.224C>T
  • LRG_1328t2:c.212C>T
  • LRG_1328:g.6923C>T
  • LRG_1328p1:p.Thr75Met
  • LRG_1328p2:p.Thr71Met
  • NC_000006.11:g.32810790G>A
  • NM_148919.3:c.224C>T
Note:
ClinGen staff contributed the HGVS expression for this variant.
Protein change:
T71M; THR75MET
Links:
OMIM: 177046.0001; dbSNP: rs748082671
NCBI 1000 Genomes Browser:
rs748082671
Molecular consequence:
  • NM_004159.5:c.212C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_148919.4:c.224C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Proteosome-associated autoinflammatory syndrome
Synonyms:
Proteasome-associated autoinflammatory syndrome
Identifiers:
MONDO: MONDO:0009726; MedGen: C1850568; OMIM: PS256040

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000957423Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 19, 2023)
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

PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome.

Agarwal AK, Xing C, DeMartino GN, Mizrachi D, Hernandez MD, Sousa AB, Martínez de Villarreal L, dos Santos HG, Garg A.

Am J Hum Genet. 2010 Dec 10;87(6):866-72. doi: 10.1016/j.ajhg.2010.10.031.

PubMed [citation]
PMID:
21129723
PMCID:
PMC2997366

Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity.

Liu Y, Ramot Y, Torrelo A, Paller AS, Si N, Babay S, Kim PW, Sheikh A, Lee CC, Chen Y, Vera A, Zhang X, Goldbach-Mansky R, Zlotogorski A.

Arthritis Rheum. 2012 Mar;64(3):895-907. doi: 10.1002/art.33368.

PubMed [citation]
PMID:
21953331
PMCID:
PMC3278554
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000957423.4

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

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 75 of the PSMB8 protein (p.Thr75Met). This variant is present in population databases (rs748082671, gnomAD 0.009%). This missense change has been observed in individuals with PMSB8-related conditions (PMID: 21129723, 21953331). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 659832). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PSMB8 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PSMB8 function (PMID: 26524591). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2024