NM_020919.4(ALS2):c.4897C>T (p.Gln1633Ter) AND Infantile-onset ascending hereditary spastic paralysis

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 10, 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:: RCV003502523.1

Allele description [Variation Report for NM_020919.4(ALS2):c.4897C>T (p.Gln1633Ter)]

NM_020919.4(ALS2):c.4897C>T (p.Gln1633Ter)

Gene:

ALS2:alsin Rho guanine nucleotide exchange factor ALS2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q33.1

Genomic location:

Preferred name:

NM_020919.4(ALS2):c.4897C>T (p.Gln1633Ter)

HGVS:

NC_000002.12:g.201704160G>A
NG_008775.1:g.82013C>T
NM_020919.4:c.4897C>TMANE SELECT
NP_065970.2:p.Gln1633Ter
LRG_654t1:c.4897C>T
LRG_654:g.82013C>T
LRG_654p1:p.Gln1633Ter
NC_000002.11:g.202568883G>A
NM_020919.3:c.4897C>T

Protein change:

Q1633*

Links:

dbSNP: rs797044934

NCBI 1000 Genomes Browser:

rs797044934

Molecular consequence:

NM_020919.4:c.4897C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Infantile-onset ascending hereditary spastic paralysis (IAHSP)
Synonyms:: Spastic paralysis, infantile onset ascending; Autosomal Recessive Juvenile Amyotrophic Lateral Sclerosis
Identifiers:: MONDO: MONDO:0011797; MedGen: C2931441; Orphanet: 293168; OMIM: 607225

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004293041	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25131622, 25356970, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004293041

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 10, 2023)

germline

clinical testing

PubMed (3)
[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

Clinical whole exome sequencing in child neurology practice.

Srivastava S, Cohen JS, Vernon H, Barañano K, McClellan R, Jamal L, Naidu S, Fatemi A.

Ann Neurol. 2014 Oct;76(4):473-83. doi: 10.1002/ana.24251. Epub 2014 Aug 30.

PubMed [citation]

PMID:: 25131622

Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions.

Farwell KD, Shahmirzadi L, El-Khechen D, Powis Z, Chao EC, Tippin Davis B, Baxter RM, Zeng W, Mroske C, Parra MC, Gandomi SK, Lu I, Li X, Lu H, Lu HM, Salvador D, Ruble D, Lao M, Fischbach S, Wen J, Lee S, Elliott A, et al.

Genet Med. 2015 Jul;17(7):578-86. doi: 10.1038/gim.2014.154. Epub 2014 Nov 13.

PubMed [citation]

PMID:: 25356970

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004293041.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Gln1633*) in the ALS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the ALS2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 25131622, 25356970). ClinVar contains an entry for this variant (Variation ID: 208757). This variant disrupts a region of the ALS2 protein in which other variant(s) (p.Gln1637*) have been observed in individuals with ALS2-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Feb 20, 2024

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