chr10-49474074-A-T

Variant names:

• chr10-49474074-A-T
• rs368728467
• NM_000124.4:c.2551T>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1_Very_Strong PM2 PP3_Strong PP5_Very_Strong

The NM_000124.4(ERCC6):​c.2551T>A​(p.Trp851Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.32
• Publications: 11 publications found

Genes affected

ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]

ERCC6 Gene-Disease associations (from GenCC):

• Cockayne spectrum with or without cerebrooculofacioskeletal syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Cockayne syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, Orphanet, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• UV-sensitive syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• UV-sensitive syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• premature ovarian failure 11

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS1: Transcript NM_000124.4 (ERCC6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 10-49474074-A-T is Pathogenic according to our data. Variant chr10-49474074-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 522698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000124.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	NM_000124.4	MANE Select	c.2551T>A	p.Trp851Arg	missense	Exon 13 of 21	NP_000115.1
	ERCC6	NM_001346440.2		c.2551T>A	p.Trp851Arg	missense	Exon 13 of 21	NP_001333369.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.2551T>A	p.Trp851Arg	missense	Exon 13 of 21	ENSP00000348089.5
	ERCC6	ENST00000623073.3	TSL:1	n.6935T>A		non_coding_transcript_exon	Exon 7 of 15
	ERCC6	ENST00000624341.3	TSL:1	n.*150T>A		non_coding_transcript_exon	Exon 3 of 11	ENSP00000485163.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cockayne syndrome type 2 Pathogenic:4

Nov 14, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 31, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.0.0 dataset. Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 9443879). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.83 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000522698 /PMID: 9443879). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 29572252). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 02, 2024

Department of Animal Biology, Molecular and Human Genetics Lab, University of Tabriz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The study of the W851R mutation in the ERCC6 gene is central to understanding the complex pathophysiological processes associated with Cockayne Syndrome (CS). While this variant has been noted in earlier research, its specific impact on the structural integrity of the ERCC6 protein and subsequent changes in its ATPase activity have not been thoroughly examined until now. Our research represents the initial effort to fully analyze the severe consequences of this missense mutation, which appears deceptively benign. Previous studies (Mallery 1998, Laugel 2010, Batenburg 2015) have highlighted the profound negative effects of the W851R mutation on ERCC6 functionality. It has been demonstrated that this mutation results in an ERCC6 protein that lacks DNA-dependent ATPase activity, leading to a disruption in chromatin remodeling and hindering essential repair processes. These findings align with our molecular dynamic simulations, which indicate compromised ATPase and DNA binding functions of the protein.

Cerebrooculofacioskeletal syndrome 1;C0242379:Lung cancer;C0265201:DE SANCTIS-CACCHIONE SYNDROME;C0751038:Cockayne syndrome type 2;C3151063:Age related macular degeneration 5;C3551173:UV-sensitive syndrome 1;C4310783:Premature ovarian failure 11 Pathogenic:1

Jan 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Oct 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 522698). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 851 of the ERCC6 protein (p.Trp851Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cockayne syndrome (PMID: 9443879, 29572252, 32557569). This variant is also known as T2630A. 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 expected to disrupt ERCC6 protein function. Experimental studies have shown that this missense change affects ERCC6 function (PMID: 9443879). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.90		Gain of disorder (P = 0.0253)
MVP		0.94
MPC		0.69
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.92
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368728467; hg19: chr10-50682120;