NM_003900.5(SQSTM1):c.772G>A (p.Asp258Asn) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 4, 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:: RCV002050182.3

Allele description [Variation Report for NM_003900.5(SQSTM1):c.772G>A (p.Asp258Asn)]

NM_003900.5(SQSTM1):c.772G>A (p.Asp258Asn)

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.772G>A (p.Asp258Asn)

HGVS:

NC_000005.10:g.179833049G>A
NG_011342.1:g.31662G>A
NM_001142298.2:c.520G>A
NM_001142299.2:c.520G>A
NM_003900.4:c.772G>A
NM_003900.5:c.772G>AMANE SELECT
NP_001135770.1:p.Asp174Asn
NP_001135771.1:p.Asp174Asn
NP_003891.1:p.Asp258Asn
NC_000005.9:g.179260049G>A
NM_003900.5:c.772G>A

Protein change:

D174N

Links:

dbSNP: rs774986849

NCBI 1000 Genomes Browser:

rs774986849

Molecular consequence:

NM_001142298.2:c.520G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001142299.2:c.520G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003900.5:c.772G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Frontotemporal dementia and/or amyotrophic lateral sclerosis 1
Synonyms:: Frontotemporal dementia with motor neuron disease 1
Identifiers:: MONDO: MONDO:0007105; MedGen: C3888102; 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
SCV002115247	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 4, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24899140, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002115247

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 4, 2023)

germline

clinical testing

PubMed (2)
[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

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

van der Zee J, Van Langenhove T, Kovacs GG, Dillen L, Deschamps W, Engelborghs S, Matěj R, Vandenbulcke M, Sieben A, Dermaut B, Smets K, Van Damme P, Merlin C, Laureys A, Van Den Broeck M, Mattheijssens M, Peeters K, Benussi L, Binetti G, Ghidoni R, Borroni B, Padovani A, et al.

Acta Neuropathol. 2014 Sep;128(3):397-410. doi: 10.1007/s00401-014-1298-7. Epub 2014 Jun 5.

PubMed [citation]

PMID:: 24899140
PMCID:: PMC4131163

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002115247.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 258 of the SQSTM1 protein (p.Asp258Asn). This variant is present in population databases (rs774986849, gnomAD 0.007%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 24899140). ClinVar contains an entry for this variant (Variation ID: 1346690). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SQSTM1 protein function. 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: Mar 16, 2024

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