rs78635798

chr11-65720385-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_032193.4(RNASEH2C):c.205C>T(p.Arg69Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,976 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: RNASEH2C NM_032193.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 1.62

Genes affected

RNASEH2C (HGNC:24116): (ribonuclease H2 subunit C) This gene encodes a ribonuclease H subunit that can cleave ribonucleotides from RNA:DNA duplexes. Mutations in this gene cause Aicardi-Goutieres syndrome-3, a disease that causes severe neurologic dysfunction. A pseudogene for this gene has been identified on chromosome Y, near the sex determining region Y (SRY) gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a strand (size 4) in uniprot entity RNH2C_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_032193.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 11-65720385-G-A is Pathogenic according to our data. Variant chr11-65720385-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-65720385-G-A is described in Lovd as [Pathogenic]. Variant chr11-65720385-G-A is described in Lovd as [Pathogenic]. Variant chr11-65720385-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2C	NM_032193.4	c.205C>T	p.Arg69Trp	missense_variant	2/4	ENST00000308418.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2C	ENST00000308418.10	c.205C>T	p.Arg69Trp	missense_variant	2/4	1	NM_032193.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000917 AC: 23 AN: 250836 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000614

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 3 Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001260, PMID:16845400, PS1_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product(PMID: 19015152, 21177854, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.709, PP3_P). A missense variant is a common mechanism associated with Aicardi-Goutieres syndrome 3 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000092, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Aicardi-Goutieres syndrome 3, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:23322642) (PMID:16845400). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation observed in multiple patients. (PMID:17846997,16845400,20131292,23322642,29150899). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 69 of the RNASEH2C protein (p.Arg69Trp). This variant is present in population databases (rs78635798, gnomAD 0.07%). This missense change has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 16845400, 23322642, 29150899, 29239743). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1260). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RNASEH2C function (PMID: 19015152, 19034401, 31529068). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Aicardi-Goutieres syndrome 3 (MIM#610329). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (23 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ribonuclease H2 non-catalytic subunit (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity. It has been reported in more than 30 patients in a homozygous state and is likely a founder mutation in the South Asian population (ClinVar, PMIDs: 17846997, 20131292, 29150899). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant causes a decrease in RNase enzyme activity and stability (PMIDs: 19015152, 31529068). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Homozygote Missense variant c.205C>T in Exon 2 of the RNASEH2C gene that results in the amino acid substitution p.Arg69Trp was identified. The observed variant has allele frequency of 0.00009/0.00 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic(ClinVar ID: 1260). Functional studies demonstrate that R69W is associated with decreased enzyme activity and reduced thermal stability of RNaseH2 (Chon H et al., 2009). c.205C>T has been reported in the literature as a homozygous genotype in multiple individuals affected with Aicardi Goutieres Syndrome and is reported as a frequent founder mutation of Asian origin (Kaur P et al., 2021 and Rice G et al., 2007). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R69W in RNASEH2C (NM_032193.3) has been reported previously in the homozygous state in multiple individuals from South Asia. It has been classified as a possible founder varint in the Asian population (Hebbar et al., 2018).Functional studies demonstrate that R69W is associated with decreased enzyme activity and reduced thermal stability of RNaseH2 .The R69W variant is observed in 21/30,782 (0.068%) alleles from individuals of South Asian background in large population cohorts (Reijns et al., 2011).There is a moderate physicochemical difference between arginine and tryptophan. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 04, 2022	A homozygous missense variation in exon 2 of the RNASEH2C gene that results in the amino acid substitution of Valine for Arginine at codon 69 was detected. The observed variant c.205C>T (p.Arg69Trp) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Feb 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 06, 2022	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2020	Published functional studies demonstrate that R69W is associated with decreased enzyme activity and reduced thermal stability of RNaseH2 (Chon et al., 2009; Reijns et al., 2011); This variant is associated with the following publications: (PMID: 25604658, 31529068, 29239743, 17846997, 21177854, 19034401, 19015152, 26456534, 23322642, 20131292, 16845400, 29150899, 27391121, 24123366, 29302074, 32180488) -

Aicardi Goutieres syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 26, 2022

Variant summary: RNASEH2C c.205C>T (p.Arg69Trp) results in a non-conservative amino acid change in 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 9.2e-05 in 250836 control chromosomes, predominantly at a frequency of 0.00072 within the South Asian subpopulation in the gnomAD database. c.205C>T has been reported in the literature as a homozygous genotype in multiple individuals affected with Aicardi Goutieres Syndrome and is reported as a frequent founder mutation of Asian origin (example, Rice_2007, Vogt_2013, Kaur_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Nishimura_2019). Nine 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Abnormality of the nervous system Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Benign	0.14
Eigen_PC	Benign	-0.033
FATHMM_MKL	Benign	0.48	N
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	0.93	A;A;A
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		1.0	D;.
Vest4		0.66
MutPred		0.88		Loss of disorder (P = 0.0022);Loss of disorder (P = 0.0022);
MVP		0.99
MPC		1.2
ClinPred		0.70	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.92
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs78635798; hg19: chr11-65487856;