NM_013444.4(UBQLN2):c.1489C>T (p.Pro497Ser) AND Amyotrophic lateral sclerosis type 15

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 27, 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:: RCV000022843.15

Allele description [Variation Report for NM_013444.4(UBQLN2):c.1489C>T (p.Pro497Ser)]

NM_013444.4(UBQLN2):c.1489C>T (p.Pro497Ser)

Gene:

UBQLN2:ubiquilin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.21

Genomic location:

Preferred name:

NM_013444.4(UBQLN2):c.1489C>T (p.Pro497Ser)

HGVS:

NC_000023.11:g.56565362C>T
NG_016249.1:g.6770C>T
NM_013444.4:c.1489C>TMANE SELECT
NP_038472.2:p.Pro497Ser
LRG_665:g.6770C>T
NC_000023.10:g.56591795C>T
Q9UHD9:p.Pro497Ser

Protein change:

P497S; PRO497SER

Links:

UniProtKB: Q9UHD9#VAR_066563; OMIM: 300264.0002; dbSNP: rs387906710

NCBI 1000 Genomes Browser:

rs387906710

Molecular consequence:

NM_013444.4:c.1489C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Amyotrophic lateral sclerosis type 15
Synonyms:: Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia; AMYOTROPHIC LATERAL SCLEROSIS 15 WITH FRONTOTEMPORAL DEMENTIA
Identifiers:: MONDO: MONDO:0010459; MedGen: C3275459; Orphanet: 803; OMIM: 300857

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000044132	OMIM	no assertion criteria provided	Pathogenic (Aug 21, 2011)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004299578	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21857683, 24215460, 25398946, 30348461, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000044132

OMIM

no assertion criteria provided

Pathogenic
(Aug 21, 2011)

germline

literature only

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

SCV004299578

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 27, 2023)

germline

clinical testing

PubMed (5)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia.

Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, et al.

Nature. 2011 Aug 21;477(7363):211-5. doi: 10.1038/nature10353.

PubMed [citation]

PMID:: 21857683
PMCID:: PMC3169705

Pathogenic mutation of UBQLN2 impairs its interaction with UBXD8 and disrupts endoplasmic reticulum-associated protein degradation.

Xia Y, Yan LH, Huang B, Liu M, Liu X, Huang C.

J Neurochem. 2014 Apr;129(1):99-106. doi: 10.1111/jnc.12606. Epub 2013 Nov 22.

PubMed [citation]

PMID:: 24215460

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000044132.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 3-generation family with apparently autosomal dominant ALS but without male-to-male transmission (ALS15; 300857), Deng et al. (2011) identified a C-to-T transition at nucleotide 1489 of the UBQLN2 gene, resulting in a pro-to-ser substitution at codon 497 (P497S) of ubiquilin-2. This mutation was not identified in 928 control samples. Half of the patients in this family had ALS with dementia.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004299578.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 497 of the UBQLN2 protein (p.Pro497Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 21857683). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29951). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the p.Pro497 amino acid residue in UBQLN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21857683, 24215460, 25398946, 30348461). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024

ClinVar

Relating variation to medicine