NM_003900.5(SQSTM1):c.1159C>G (p.Pro387Ala) AND Frontotemporal dementia and/or amyotrophic lateral sclerosis 3

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 24, 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:: RCV003323343.2

Allele description [Variation Report for NM_003900.5(SQSTM1):c.1159C>G (p.Pro387Ala)]

NM_003900.5(SQSTM1):c.1159C>G (p.Pro387Ala)

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.1159C>G (p.Pro387Ala)

HGVS:

NC_000005.10:g.179833776C>G
NG_011342.1:g.32389C>G
NM_001142298.2:c.907C>G
NM_001142299.2:c.907C>G
NM_003900.5:c.1159C>GMANE SELECT
NP_001135770.1:p.Pro303Ala
NP_001135771.1:p.Pro303Ala
NP_003891.1:p.Pro387Ala
NC_000005.9:g.179260776C>G

Protein change:

P303A

Molecular consequence:

NM_001142298.2:c.907C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001142299.2:c.907C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_003900.5:c.1159C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3
Synonyms:: FTDALS3
Identifiers:: MONDO: MONDO:0014640; MedGen: C4225326; Orphanet: 275864; Orphanet: 275872; Orphanet: 803; OMIM: 616437

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004028533	Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 24, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 35047667

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004028533

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 24, 2023)

unknown

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	unknown	yes	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Revealing the Mutational Spectrum in Southern Africans With Amyotrophic Lateral Sclerosis.

Nel M, Mahungu AC, Monnakgotla N, Botha GR, Mulder NJ, Wu G, Rampersaud E, van Blitterswijk M, Wuu J, Cooley A, Myers J, Rademakers R, Taylor JP, Benatar M, Heckmann JM.

Neurol Genet. 2022 Feb;8(1):e654. doi: 10.1212/NXG.0000000000000654.

PubMed [citation]

PMID:: 35047667
PMCID:: PMC8756565

Details of each submission

From Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology, SCV004028533.1

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

Description

The c.1159C>G variant is not present in publicly available population databases like 1000 Genomes, EVS, Indian Exome Database or our in-house exome database. The variant is present in ExAC and gnomAD at low frequencies. This variant has been previously observed in South African patient(s) affected with amyotrophic lateral sclerosis and published in the literature [PMID:35047667]. It has not been reported to the clinical databases like ClinVar, Human Genome Mutation Database (HGMD) or OMIM, in any affected individuals. In-silico pathogenicity programs like SIFT, PolyPhen-2, MutationTaster2, CADD, Varsome etc predicted this variant to be likely deleterious however these predictions were not confirmed by published functional studies. An alternative variant with a different amino acid change in the same codon (c.1160C>T, Pro387Leu) has been previously observed in individuals affected with SQSTM1-related conditions, published several times in literature and reported to the clinical databases as ‘pathogenic / likely pathogenic / uncertain significance’ by multiple submitters.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	1	not provided

Last Updated: Jun 23, 2024

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