rs376556895

Variant names:

• chr19-45352801-C-G
• rs376556895
• NM_000400.4:c.1847G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-45352801-C-G
• chr19-45352801-C-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM5 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 5.14
• Publications: 39 publications found

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 Gene-Disease associations (from GenCC):

• cerebrooculofacioskeletal syndrome 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• trichothiodystrophy 1, photosensitive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• xeroderma pigmentosum group D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• sarcoma

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-45352801-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 997520.
• 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 VariationId is 329508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1847G>C	p.Arg616Pro	missense_variant	Exon 20 of 23	ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1847G>C	p.Arg616Pro	missense_variant	Exon 20 of 23	1	NM_000400.4	ENSP00000375809.4

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151734 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.000151 AC: 38 AN: 250892 AF XY: 0.000125

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 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.: 0 Cov.: 37 AF XY: 0.000268 AC XY: 195 AN XY: 727080

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000367 AC: 408 AN: 1111860

Other (OTH) AF: 0.000298 AC: 18 AN: 60374

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151734 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74092

African (AFR) AF: 0.0000728 AC: 3 AN: 41228

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67932

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Apr 24, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (PMID: 9238033); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7920640, 23221806, 24448499, 7585650, 24252196, 12393803, 23800062, 9238033, 29478780, 26556299, 31738647, 30860024, 31110295, 36493725, 31589614, 33976420, 31794323, 33858029, 32191290, 34308104, 36033485, 35833951, 11734544, 37410378, 26884178, 27004399, 11710928, 30625039, 12820975) -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ERCC2: PS3, PM1, PM5, PP3 -

Sep 19, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Xeroderma pigmentosum Pathogenic:3

May 21, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 28, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 24, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 29, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cerebrooculofacioskeletal syndrome 2 Pathogenic:1

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Xeroderma pigmentosum, group D Pathogenic:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
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	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;.;.
PhyloP100		5.1
PrimateAI	Pathogenic	0.82	D
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	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.97
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs376556895; hg19: chr19-45856059; COSMIC: COSV67268805; COSMIC: COSV67268805;