rs376556895

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000400.4(ERCC2):c.1847G>C(p.Arg616Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000283 in 1,613,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R616Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.14

Variant links:

Genes affected

ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ERCC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a strand (size 4) in uniprot entity ERCC2_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000400.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-45352802-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 19-45352801-C-G is Pathogenic according to our data. Variant chr19-45352801-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 329508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45352801-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ERCC2	NM_000400.4 linkuse as main transcript	c.1847G>C	p.Arg616Pro	missense_variant	20/23	ENST00000391945.10
ERCC2	XM_011526611.3 linkuse as main transcript	c.1769G>C	p.Arg590Pro	missense_variant	19/22
ERCC2	XR_001753633.3 linkuse as main transcript	n.1880G>C		non_coding_transcript_exon_variant	20/24
ERCC2	XR_007066680.1 linkuse as main transcript	n.1802G>C		non_coding_transcript_exon_variant	19/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10 linkuse as main transcript	c.1847G>C	p.Arg616Pro	missense_variant	20/23	1	NM_000400.4	P1	P18074-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151734

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000728

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000151

AC:

AN:

250892

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000274

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000297

AC:

434

AN:

1461602

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

195

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.000367

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000145

AC:

AN:

151734

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74092

show subpopulations

Gnomad4 AFR

AF:

0.0000728

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000227

Hom.:

Bravo

AF:

0.000170

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2023	Published functional studies on the yeast Rad15 gene, which is homologous to the human ERCC2 gene, demonstrate that the yeast R616P homologous variant is a functional null allele (Taylor et al., 1997); This variant is associated with the following publications: (PMID: 7920640, 9238033, 23221806, 24448499, 7585650, 24252196, 12393803, 23800062, 29478780, 26556299, 31738647, 30860024, 31110295, 31589614, 33976420, 31794323, 33858029, 32191290, 34308104, 36033485, 35833951, 11734544, 37410378, 26884178, 27004399, 11710928, 30625039, 12820975) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 616 of the ERCC2 protein (p.Arg616Pro). This variant is present in population databases (rs376556895, gnomAD 0.03%). This missense change has been observed in individuals with xeroderma pigmentosum or trichothiodystrophy (PMID: 7920640, 9238033, 11734544, 23221806, 23800062). ClinVar contains an entry for this variant (Variation ID: 329508). 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 ERCC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ERCC2 function (PMID: 9238033, 12820975). This variant disrupts the p.Arg616 amino acid residue in ERCC2. Other variant(s) that disrupt this residue have been observed in individuals with ERCC2-related conditions (PMID: 11443545, 22234153, 23800062, 27396511), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 19, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -

Xeroderma pigmentosum

Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 28, 2020	Variant summary: ERCC2 c.1847G>C (p.Arg616Pro) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 250892 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum (0.00015 vs 0.00061), allowing no conclusion about variant significance. c.1847G>C has been reported in the literature in individuals affected with Xeroderma Pigmentosum and Trichothiodystrophy (Taylor_1997, Broughton_1994, Orioli_2013, Schafer_2013, Takayama_1996). These data indicate that the variant is likely to be associated with disease. Experimental studies have shown that the variant completely abolished basal transcription, failed to restore viability, and abolished more than 80% of excision repair activity (Dubaele_2003, Taylor_1997, Broughton_1994). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 24, 2019	The p.Arg616Pro variant in ERCC2 has been reported in the compound heterozygous state in 1 individual with trichothiodystrophy, 7 individuals with xeroderma pigmentosum, and 1 individual with Cockayne syndrome (Broughton 1994, Taylor 1997, Lai 2013, Schafer 2013, Calmels 2016). Additionally, the variant was identified in the compound heterozygous state in a sibling affected with learning disability and mild photosensitivity (Calmels 2016). The p.Arg616Pro variant has also been identified in 0.026% (34/128592) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported as Pathogenic and Likely Pathogenic in ClinVar (Variation ID 329508). In vitro functional studies support an impact on protein function (Taylor 1997, Queille 2001, Dubaele 2003). Computational prediction tools and conservation analyses also support that this variant may impact the protein. Finally, several other amino acid changes at the same position (p.Arg616Gln, p.Arg6161Gly, p.Arg616Trp) have been reported in individuals affected with ERCC2-related disorders. In summary, the p.Arg616Pro variant meets criteria to be classified as pathogenic for autosomal recessive xeroderma pigmentosum. ACMG/AMP criteria applied: PM3_Strong, PM5, PS3_Moderate, PM2_Supporting, PP1, PP3. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The c.1847G>C (p.R616P) alteration is located in exon 20 (coding exon 20) of the ERCC2 gene. This alteration results from a G to C substitution at nucleotide position 1847, causing the arginine (R) at amino acid position 616 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.01% (41/282052) total alleles studied. The highest observed frequency was 0.04% (3/7206) of Other alleles. This mutation has been observed with a second pathogenic alteration in trans in a male presenting with trichothiodystrophy and unscheduled DNA synthesis at 15% of normal and cell survival at 20% of normal after UV-irradiation (Broughton, 1994; Takayama, 1996). In addition, multiple individuals affected with ERCC2-related disorders have been described with p.R616P and a second pathogenic mutation (Takayama, 1996, Taylor, 1997, Schäfer, 2013; Calmels, 2016; Lai, 2013; Fassihi, 2016). This amino acid position is highly conserved in available vertebrate species. In vitro studies of the homolog rad15 suggests this mutation is a null allele when it was observed that this mutation could not restore cell viability when compound heterozygous with a deletion mutation (Taylor, 1997). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Xeroderma pigmentosum, group D;C1853102:Cerebrooculofacioskeletal syndrome 2;C1866504:Trichothiodystrophy 1, photosensitive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 04, 2022

- -

Cerebrooculofacioskeletal syndrome 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 25, 2023

- -

Xeroderma pigmentosum, group D

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The ERCC2 c.1847G>C (p.Arg616Pro) variant was identified in a total of 11 compound heterozygotes, including nine exhibiting a xeroderma pigmentosum (XP) phenotype, one with an XP/Cockayne syndrome phenotype, and one with trichothiodystrophy (Taylor et al. 1997; Emmert et al. 2009; Shafer et al. 2013; Lai et al. 2013; Calmels et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregation Consortium. Taylor et al. (1997) demonstrated that the p.Arg616Pro variant was unable to rescue lethality in a yeast complementation assay. When compared to control cell lines exposed to UV, fibroblasts from individuals carrying the p.Arg616Pro variant showed greater levels of apoptosis (Quielle et al. 2001) and reduced nucleotide excision repair capacity (Shafer et al. 2013), and the variant was noted to completely abolish basal transcription (Dubaele et al. 2003). Based on the collective evidence, the p.Arg616Pro variant is classified as pathogenic for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.51

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

H;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.5

D;D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.99

MVP

0.99

MPC

0.96

ClinPred

1.0

GERP RS

5.1

Varity_R

0.99

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over