NM_004960.4(FUS):c.1376C>T (p.Pro459Leu) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 15, 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:: RCV002527105.3

Allele description [Variation Report for NM_004960.4(FUS):c.1376C>T (p.Pro459Leu)]

NM_004960.4(FUS):c.1376C>T (p.Pro459Leu)

Gene:

FUS:FUS RNA binding protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p11.2

Genomic location:

Preferred name:

NM_004960.4(FUS):c.1376C>T (p.Pro459Leu)

HGVS:

NC_000016.10:g.31190825C>T
NG_012889.2:g.15694C>T
NM_001170634.1:c.1373C>T
NM_001170937.1:c.1364C>T
NM_004960.4:c.1376C>TMANE SELECT
NP_001164105.1:p.Pro458Leu
NP_001164408.1:p.Pro455Leu
NP_004951.1:p.Pro459Leu
NP_004951.1:p.Pro459Leu
LRG_655t1:c.1376C>T
LRG_655:g.15694C>T
LRG_655p1:p.Pro459Leu
NC_000016.9:g.31202146C>T
NM_004960.3:c.1376C>T
NR_028388.2:n.1446C>T

Protein change:

P455L

Links:

dbSNP: rs1131691846

NCBI 1000 Genomes Browser:

rs1131691846

Molecular consequence:

NM_001170634.1:c.1373C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001170937.1:c.1364C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004960.4:c.1376C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_028388.2:n.1446C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Amyotrophic lateral sclerosis type 6
Synonyms:: AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA; Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia; FUS-Related Amyotrophic Laterial Sclerosis
Identifiers:: MONDO: MONDO:0011951; MedGen: C2931786; Orphanet: 275872; Orphanet: 803; OMIM: 608030

Name:: Tremor, hereditary essential, 4 (ETM4)
Identifiers:: MONDO: MONDO:0013888; MedGen: C3539195; OMIM: 614782

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003453137	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 15, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30279455, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003453137

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 15, 2022)

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

Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series.

Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, et al.

Mol Psychiatry. 2020 Dec;25(12):3399-3412. doi: 10.1038/s41380-018-0224-0. Epub 2018 Oct 2.

PubMed [citation]

PMID:: 30279455
PMCID:: PMC6330090

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003453137.2

#	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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 459 of the FUS protein (p.Pro459Leu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 430234). This missense change has been observed in individual(s) with clinical features of FUS-related conditions (PMID: 30279455). This variant is present in population databases (no rsID available, gnomAD no frequency).

#	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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