NM_003900.5(SQSTM1):c.263C>T (p.Ser88Phe) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 18, 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:: RCV000791963.7

Allele description [Variation Report for NM_003900.5(SQSTM1):c.263C>T (p.Ser88Phe)]

NM_003900.5(SQSTM1):c.263C>T (p.Ser88Phe)

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.263C>T (p.Ser88Phe)

HGVS:

NC_000005.10:g.179823015C>T
NG_011342.1:g.21628C>T
NM_001142298.2:c.11C>T
NM_001142299.2:c.11C>T
NM_003900.5:c.263C>TMANE SELECT
NP_001135770.1:p.Ser4Phe
NP_001135771.1:p.Ser4Phe
NP_003891.1:p.Ser88Phe
NC_000005.9:g.179250015C>T
NM_003900.4:c.263C>T

Protein change:

S4F

Links:

dbSNP: rs763040103

NCBI 1000 Genomes Browser:

rs763040103

Molecular consequence:

NM_001142298.2:c.11C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142299.2:c.11C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003900.5:c.263C>T - 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
SCV000931234	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 18, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31859009, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000931234

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 18, 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

SQSTM1/p62 variants in 486 patients with familial ALS from Germany and Sweden.

Yilmaz R, Müller K, Brenner D, Volk AE, Borck G, Hermann A, Meitinger T, Strom TM, Danzer KM, Ludolph AC, Andersen PM, Weishaupt JH; German ALS Network MND-NET..

Neurobiol Aging. 2020 Mar;87:139.e9-139.e15. doi: 10.1016/j.neurobiolaging.2019.10.018. Epub 2019 Nov 2.

PubMed [citation]

PMID:: 31859009

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, SCV000931234.7

#	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 serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 88 of the SQSTM1 protein (p.Ser88Phe). This variant is present in population databases (rs763040103, gnomAD 0.006%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 31859009). ClinVar contains an entry for this variant (Variation ID: 639220). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SQSTM1 protein function with a negative predictive value of 80%. 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 5, 2024

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