NM_004181.5(UCHL1):c.349_364del (p.Phe117fs) AND Spastic paraplegia 79A, autosomal dominant, with ataxia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 30, 2024
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV003152622.4

Allele description [Variation Report for NM_004181.5(UCHL1):c.349_364del (p.Phe117fs)]

NM_004181.5(UCHL1):c.349_364del (p.Phe117fs)

Gene:

UCHL1:ubiquitin C-terminal hydrolase L1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

4p13

Genomic location:

Preferred name:

NM_004181.5(UCHL1):c.349_364del (p.Phe117fs)

HGVS:

NC_000004.12:g.41261738_41261753del
NG_012931.1:g.9858_9873del
NM_004181.5:c.349_364delMANE SELECT
NP_004172.2:p.Phe117fs
NC_000004.11:g.41263755_41263770del
NM_004181.4:c.349_364del

Protein change:

F117fs

Links:

OMIM: 191342.0007; dbSNP: rs1781070341

NCBI 1000 Genomes Browser:

rs1781070341

Molecular consequence:

NM_004181.5:c.349_364del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Spastic paraplegia 79A, autosomal dominant, with ataxia (SPG79A)
Synonyms:: Spastic paraplegia 79A, autosomal dominant
Identifiers:: MONDO: MONDO:0859363; MedGen: C5774300; OMIM: 620221

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003840997	OMIM	no assertion criteria provided	Pathogenic (Jan 30, 2024)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003840997

OMIM

no assertion criteria provided

Pathogenic
(Jan 30, 2024)

germline

literature only

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

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

Citations

PubMed

Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.

Park J, Tucci A, Cipriani V, Demidov G, Rocca C, Senderek J, Butryn M, Velic A, Lam T, Galanaki E, Cali E, Vestito L, Maroofian R, Deininger N, Rautenberg M, Admard J, Hahn GA, Bartels C, van Os NJH, Horvath R, Chinnery PF, Tiet MY, et al.

Genet Med. 2023 Oct;25(10):100961. doi: 10.1016/j.gim.2023.100961. Epub 2023 Aug 31. No abstract available.

PubMed [citation]

PMID:: 37650884

Details of each submission

From OMIM, SCV003840997.3

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

Description

In 4 affected members of a multigenerational family (family 2) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified a heterozygous 16-bp deletion (c.349_364del, NM_004181.4) in the UCHL1 gene, resulting in a frameshift and premature termination (Phe117ArgfsTer33). The mutation, which was found by diagnostic exome and genome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but mass spectrometry analysis of patient fibroblasts showed a significant decrease in UCHL1 protein levels, suggesting that haploinsufficiency for this gene is the pathogenetic mechanism for this phenotype. One of the patients in this family had an additional diagnosis of ALS (105400) and carried a heterozygous pathogenic missense mutation (D91A) in the SOD1 gene (147450).

#	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

Last Updated: Oct 20, 2024

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