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:: RCV003596608.1

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000957423	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21129723, 21953331, 26524591, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000957423

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 19, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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 Invitae, SCV000957423.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 19, 2024

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