NM_001378743.1(CYLD):c.1112C>A (p.Ser371Ter) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 13, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000760471.2

Allele description

NM_001378743.1(CYLD):c.1112C>A (p.Ser371Ter)

Gene:

CYLD:CYLD lysine 63 deubiquitinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q12.1

Genomic location:

Preferred name:

NM_001378743.1(CYLD):c.1112C>A (p.Ser371Ter)

HGVS:

NC_000016.10:g.50777915C>A
NG_012061.1:g.40866C>A
NM_001042355.2:c.1103C>A
NM_001042412.3:c.1103C>A
NM_001378743.1:c.1112C>AMANE SELECT
NM_001378744.1:c.1103C>A
NM_001378745.1:c.1103C>A
NM_001378746.1:c.1103C>A
NM_001378747.1:c.1103C>A
NM_001378748.1:c.1103C>A
NM_001378749.1:c.1103C>A
NM_001378750.1:c.1103C>A
NM_001378751.1:c.1103C>A
NM_001378752.1:c.1103C>A
NM_001378753.1:c.1103C>A
NM_001378754.1:c.437C>A
NM_001378755.1:c.437C>A
NM_015247.3:c.1112C>A
NP_001035814.1:p.Ser368Ter
NP_001035877.1:p.Ser368Ter
NP_001365672.1:p.Ser371Ter
NP_001365673.1:p.Ser368Ter
NP_001365674.1:p.Ser368Ter
NP_001365675.1:p.Ser368Ter
NP_001365676.1:p.Ser368Ter
NP_001365677.1:p.Ser368Ter
NP_001365678.1:p.Ser368Ter
NP_001365679.1:p.Ser368Ter
NP_001365680.1:p.Ser368Ter
NP_001365681.1:p.Ser368Ter
NP_001365682.1:p.Ser368Ter
NP_001365683.1:p.Ser146Ter
NP_001365684.1:p.Ser146Ter
NP_056062.1:p.Ser371Ter
NP_056062.1:p.Ser371Ter
LRG_491t1:c.1112C>A
LRG_491:g.40866C>A
LRG_491p1:p.Ser371Ter
NC_000016.9:g.50811826C>A
NM_015247.2:c.1112C>A
NR_166071.1:n.1367C>A
p.[Ser371*]

Protein change:

S146*

Links:

dbSNP: rs886040872

NCBI 1000 Genomes Browser:

rs886040872

Molecular consequence:

NR_166071.1:n.1367C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001042355.2:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001042412.3:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378743.1:c.1112C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378744.1:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378745.1:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378746.1:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378747.1:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378748.1:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378749.1:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378750.1:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378751.1:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378752.1:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378753.1:c.1103C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378754.1:c.437C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001378755.1:c.437C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_015247.3:c.1112C>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000890360	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Dec 18, 2018)	germline	clinical testing	Citation Link,
SCV004297725	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 13, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19462465, 10835629, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000890360

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Dec 18, 2018)

germline

clinical testing

Citation Link,

SCV004297725

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 13, 2024)

germline

clinical testing

PubMed (3)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling.

Blake PW, Toro JR.

Hum Mutat. 2009 Jul;30(7):1025-36. doi: 10.1002/humu.21024. Review.

PubMed [citation]

PMID:: 19462465
PMCID:: PMC3243308

Identification of the familial cylindromatosis tumour-suppressor gene.

Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R, Green H, Brown C, Biggs PJ, Lakhani SR, Jones C, Hansen J, Blair E, Hofmann B, Siebert R, Turner G, Evans DG, Schrander-Stumpel C, Beemer FA, van Den Ouweland A, Halley D, Delpech B, et al.

Nat Genet. 2000 Jun;25(2):160-5.

PubMed [citation]

PMID:: 10835629

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000890360.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The S371X variant in the CYLD gene has been reported previously in multiple unrelated individuals with either Brooke-Spiegler syndrome, familial cylindromatosis, or multiple familial trichoepitheliomas (Bignell et al., 2000; Bowen et al., 2005; Kazakov et al., 2011; Linos et al., 2011; Grossman et al., 2013; Lv et al., 2014; Dubois et al., 2017; Monteiro et al., 2018a; Monteiro et al., 2018b). The S371X is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The S371X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret S371X as a pathogenic variant.

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

From Invitae, SCV004297725.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Ser371*) in the CYLD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYLD are known to be pathogenic (PMID: 19462465). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with familial cylindromatosis (PMID: 10835629). ClinVar contains an entry for this variant (Variation ID: 267232). For these reasons, this variant has been classified as Pathogenic.

#	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 16, 2024

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