NM_003900.5(SQSTM1):c.1165+1G>A AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 2, 2022
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:: RCV000652541.13

Allele description [Variation Report for NM_003900.5(SQSTM1):c.1165+1G>A]

NM_003900.5(SQSTM1):c.1165+1G>A

Gene:

SQSTM1:sequestosome 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q35.3

Genomic location:

Preferred name:

NM_003900.5(SQSTM1):c.1165+1G>A

HGVS:

NC_000005.10:g.179833783G>A
NG_011342.1:g.32396G>A
NM_001142298.2:c.913+1G>A
NM_001142299.2:c.913+1G>A
NM_003900.5:c.1165+1G>AMANE SELECT
NC_000005.9:g.179260783G>A
NC_000005.9:g.179260783G>A
NM_003900.4:c.970_1165del

Note:

NCBI staff reviewed the sequence information reported in PubMed 12374763 Fig. 1 to determine the location of this allele on the current reference sequence.

Nucleotide change:

IVS7DS, G-A, +1

Links:

OMIM: 601530.0003; dbSNP: rs796051870

NCBI 1000 Genomes Browser:

rs796051870

Molecular consequence:

NM_001142298.2:c.913+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001142299.2:c.913+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_003900.5:c.1165+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1)
Synonyms:: Frontotemporal dementia with motor neuron disease 1
Identifiers:: MONDO: MONDO:0007105; MedGen: C5779877; Orphanet: 275872; OMIM: 105550

Name:: Paget disease of bone 2, early-onset (PDB2)
Synonyms:: Paget disease of bone 2
Identifiers:: MONDO: MONDO:0011183; MedGen: C4085251; OMIM: 602080

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000774411	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 2, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 12374763, 17129171, 23417734, 26208961, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000774411

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 2, 2022)

germline

clinical testing

PubMed (6)
[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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease.

Hocking LJ, Lucas GJ, Daroszewska A, Mangion J, Olavesen M, Cundy T, Nicholson GC, Ward L, Bennett ST, Wuyts W, Van Hul W, Ralston SH.

Hum Mol Genet. 2002 Oct 15;11(22):2735-9.

PubMed [citation]

PMID:: 12374763

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000774411.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change affects a donor splice site in intron 7 of the SQSTM1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SQSTM1 cause disease. For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products leading to truncation of C-terminal protein domains (PMID: 26208961). ClinVar contains an entry for this variant (Variation ID: 8110). This variant is also known as A390X. Disruption of this splice site has been observed in individuals with autosomal dominant SQSTM1-related conditions (PMID: 12374763, 17129171, 23417734, 26208961). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs796051870, gnomAD 0.0009%).

#	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

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