NM_000124.4(ERCC6):c.3952_3953del (p.Arg1318fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 29, 2023
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:: RCV001231998.10

Allele description [Variation Report for NM_000124.4(ERCC6):c.3952_3953del (p.Arg1318fs)]

NM_000124.4(ERCC6):c.3952_3953del (p.Arg1318fs)

Gene:

ERCC6:ERCC excision repair 6, chromatin remodeling factor [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

10q11.23

Genomic location:

Preferred name:

NM_000124.4(ERCC6):c.3952_3953del (p.Arg1318fs)

HGVS:

NC_000010.11:g.49461382_49461383del
NG_009442.1:g.82719_82720del
NM_000124.4:c.3952_3953delMANE SELECT
NM_001346440.2:c.3952_3953del
NP_000115.1:p.Arg1318fs
NP_001333369.1:p.Arg1318fs
LRG_465t1:c.3952_3953del
LRG_465:g.82719_82720del
NC_000010.10:g.50669428_50669429del
NM_000124.2:c.3952_3953del
NM_000124.2:c.3952_3953delAG
NM_000124.3:c.3952_3953del
NM_000124.3:c.3952_3953delAG
NM_000124.4:c.3952_3953delAGMANE SELECT

Protein change:

R1318fs

Links:

dbSNP: rs765825423

NCBI 1000 Genomes Browser:

rs765825423

Molecular consequence:

NM_000124.4:c.3952_3953del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001346440.2:c.3952_3953del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001404539	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 29, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18628313, 29572252, 28492532
SCV001983862	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 18, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001404539

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 29, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001983862

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 18, 2023)

germline

clinical testing

Citation Link

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

Cerebro-oculo-facio-skeletal syndrome: three additional cases with CSB mutations, new diagnostic criteria and an approach to investigation.

Laugel V, Dalloz C, Tobias ES, Tolmie JL, Martin-Coignard D, Drouin-Garraud V, Valayannopoulos V, Sarasin A, Dollfus H.

J Med Genet. 2008 Sep;45(9):564-71. doi: 10.1136/jmg.2007.057141. Epub 2008 Jul 15.

PubMed [citation]

PMID:: 18628313

Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome.

Calmels N, Botta E, Jia N, Fawcett H, Nardo T, Nakazawa Y, Lanzafame M, Moriwaki S, Sugita K, Kubota M, Obringer C, Spitz MA, Stefanini M, Laugel V, Orioli D, Ogi T, Lehmann AR.

J Med Genet. 2018 May;55(5):329-343. doi: 10.1136/jmedgenet-2017-104877. Epub 2018 Mar 23.

PubMed [citation]

PMID:: 29572252

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001404539.5

#	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.Arg1318Glyfs*12) in the ERCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 18628313, 29572252). This variant is present in population databases (rs765825423, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Cockayne syndrome type B (PMID: 29572252). ClinVar contains an entry for this variant (Variation ID: 190171). 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

From GeneDx, SCV001983862.4

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

Description

Reported in two unrelated patients with Cockayne syndrome who each harbored another variant in the ERCC6 gene in published literature (Calmels et al., 2018); Identified in a patient with a clinical diagnosis and family history of hearing loss, loss of ambulation, hypotonia, cerebellar ataxia and sensory neuropathy who underwent exome sequencing (Monies et al., 2019); this individual also harbored an intronic variant in ERCC6 though its clinical significance was considered to be unknown; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31130284, 29572252, 18628313, 9443879)

#	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

Last Updated: May 7, 2024

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