Submissions for variant NM_006831.3(CLP1):c.419G>A (p.Arg140His)

dbSNP: rs587777616

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000133463	SCV000256728	likely pathogenic	Pontocerebellar hypoplasia type 10	2014-04-27	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000658593	SCV000780370	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	CLP1: PP1:Strong, PM2, PM3, PS3:Moderate
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000133463	SCV001164425	pathogenic	Pontocerebellar hypoplasia type 10	2018-12-03	criteria provided, single submitter	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).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000133463	SCV001443054	pathogenic	Pontocerebellar hypoplasia type 10	2023-11-28	criteria provided, single submitter	clinical testing	Criteria applied: PP1_STR,PS3_MOD,PM3,PM2_SUP,PP3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000658593	SCV001446575	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000133463	SCV002073193	pathogenic	Pontocerebellar hypoplasia type 10		criteria provided, single submitter	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
Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences	RCV000133463	SCV003926588	pathogenic	Pontocerebellar hypoplasia type 10	2023-05-27	criteria provided, single submitter	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.
OMIM	RCV000133463	SCV000188498	pathogenic	Pontocerebellar hypoplasia type 10	2014-04-24	no assertion criteria provided	literature only