rs587777616

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_006831.3(CLP1):c.419G>A(p.Arg140His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,864 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: not found (cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CLP1
NM_006831.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.98

Publications

29 publications found

Variant links:

Genes affected

CLP1 (HGNC:16999): (cleavage factor polyribonucleotide kinase subunit 1) This gene encodes a member of the Clp1 family. The encoded protein is a multifunctional kinase which is a component of the tRNA splicing endonuclease complex and a component of the pre-mRNA cleavage complex II. This protein is implicated in tRNA, mRNA, and siRNA maturation. Mutations in this gene are associated with pontocerebellar hypoplasia type 10 (PCH10). Alternatively splice transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

CLP1 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 10
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia

CLP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

PP5

Variant 11-57659895-G-A is Pathogenic according to our data. Variant chr11-57659895-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 143934.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
CLP1	NM_006831.3 link	c.419G>A	p.Arg140His	missense_variant	Exon 2 of 3	ENST00000533682.2	NP_006822.1	Q92989-1
CLP1	NM_001142597.2 link	c.414+5G>A		splice_region_variant, intron_variant	Intron 2 of 2		NP_001136069.1	Q92989-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLP1	ENST00000533682.2 link	c.419G>A	p.Arg140His	missense_variant	Exon 2 of 3	1	NM_006831.3	ENSP00000434995.1		Q92989-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251204

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111998

Other (OTH)

AF:

0.0000497

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000473

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 10

Pathogenic:6

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.R140H in CLP1 (NM_006831.3) has been reported in multiple individuals of Turkish origin and has been classified as a Founder variant in the same population (Schaffer AE et al). Functional studies revealed a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The p.R140H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 140 of CLP1 is conserved in all mammalian species. The nucleotide c.419 in CLP1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -

Apr 24, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 27, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Nov 28, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PP1_STR,PS3_MOD,PM3,PM2_SUP,PP3 -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Arg140His variant in CLP1 was identified by our study in one individual with pontocerebellar hypoplasia. This variant has been identified in 0.002978% (1/33574) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587777616). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The homozygous p.Arg140His variant in CLP1 has been reported in 19 Turkish individuals with cerebellar abnormalities and segregated with disease in 19 affected relatives from 9 families (PMID: 24766809, 24766810). In vitro functional studies provide some evidence that the p.Arg140His variant may impact protein function by impairing protein interaction with TSEN and reducing pre-tRNA cleavage activity. Northern blot analysis of individuals homozygous and heterozygous for this variant demonstrated increased levels of linear tRNA introns in individuals with the variant in the homozygous state (PMID: 24766809, 24766810). However, these types of assays may not accurately represent biological function. Animal models in zebrafish have shown that the wildtype gene, but not this variant, can rescue cerebellar neurodegeneration and animal models in mice have shown that this variant casues pontocerebellar hypoplasia (PMID: 24766809, 24766810). In summary, this variant meets criteria to be classified as pathogenic for Pontocerebellar Hypoplasia in an autosomal recessive manner based on evidence from in vitro functional studies, animal models in mice and zebrafish, and multiple occurrences of cosegregation in Turkish families. ACMG/AMP Criteria applied: PM2, PS3, PP1_Strong, PP3 (Richards 2015). -

May 27, 2023

Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R140H variant in CLP1 gene has been identified in two Iranian families with seizure, brain and cerebellar atrophy, leukodystrophy, hypotonia, and developmental and motor delay. -

not provided

Pathogenic:4

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLP1: PP1:Strong, PM2, PM3, PS3:Moderate -

Dec 15, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect on protein function (PMID: 35139363, 24766809, 24766810); Not observed at significant frequency in large population cohorts (gnomAD); 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: 29307788, 24766809, 24766810, 34548404, 38622473, 34273619, 35156311, 25142875, 32143824, Ozcora2020[article], 34791078, 33337366, 38925092, 34584079, 37231152, 35139363, 36076253, 35719383, 38347586, 28097321, 34582790, Ibrahimoglu2024[abstract]) -

Pontoneocerebellar hypoplasia

Pathogenic:1

Jun 27, 2025

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CLP1 c.419G>A (p.Arg140His) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4e-06 in 251204 control chromosomes. c.419G>A has been observed at a homozygous state in multiple families affected with progressive brain atrophy, cerebellar development delay and neurodegeneration (example, Schaffer_2014). 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. The most pronounced variant effect results in less than 50% of normal activity in vitro (Schaffer_2014). The following publication has been ascertained in the context of this evaluation (PMID: 24766810). ClinVar contains an entry for this variant (Variation ID: 143934). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

T;T;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;.;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.5

.;M;M

PhyloP100

8.0

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.89

MutPred

0.61

.;Loss of MoRF binding (P = 0.0104);Loss of MoRF binding (P = 0.0104);

MVP

0.62

MPC

1.8

ClinPred

0.98

GERP RS

4.9

Varity_R

0.89

gMVP

0.76

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over