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NM_025077.4(TOE1):c.551G>T (p.Arg184Leu) AND Pontocerebellar hypoplasia type 7

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 19, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001682617.2

Allele description [Variation Report for NM_025077.4(TOE1):c.551G>T (p.Arg184Leu)]

NM_025077.4(TOE1):c.551G>T (p.Arg184Leu)

Gene:
TOE1:target of EGR1, exonuclease [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p34.1
Genomic location:
Preferred name:
NM_025077.4(TOE1):c.551G>T (p.Arg184Leu)
HGVS:
  • NC_000001.11:g.45342442G>T
  • NG_008189.1:g.3029C>A
  • NM_025077.4:c.551G>TMANE SELECT
  • NP_079353.3:p.Arg184Leu
  • LRG_220:g.3029C>A
  • NC_000001.10:g.45808114G>T
  • NM_025077.3:c.551G>T
Protein change:
R184L
Links:
dbSNP: rs267598623
NCBI 1000 Genomes Browser:
rs267598623
Molecular consequence:
  • NM_025077.4:c.551G>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Pontocerebellar hypoplasia type 7
Identifiers:
MONDO: MONDO:0013993; MedGen: C3554226; Orphanet: 284339; OMIM: 614969

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001895909Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Sep 19, 2021) 		paternalclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedpaternalyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.

Lardelli RM, Schaffer AE, Eggens VR, Zaki MS, Grainger S, Sathe S, Van Nostrand EL, Schlachetzki Z, Rosti B, Akizu N, Scott E, Silhavy JL, Heckman LD, Rosti RO, Dikoglu E, Gregor A, Guemez-Gamboa A, Musaev D, Mande R, Widjaja A, Shaw TL, Markmiller S, et al.

Nat Genet. 2017 Mar;49(3):457-464. doi: 10.1038/ng.3762. Epub 2017 Jan 16.

PubMed [citation]
PMID:
28092684
PMCID:
PMC5325768

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, SCV001895909.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedclinical testing PubMed (2)

Description

The c.551G>T, p.Arg184Leu variant was identified in a Chinese patient with PCH7, who yet harbored another heterozygous splicing variant of c.237-2A>G . The splicing variant was inherited from mother, while the missense variant was de novo. TA clone sequencing confirmed the missense variant occurred on the paternal strand of the patient. The c.551G>T, p.Arg184Leu variant located at exon 6 of TOE1 was not present in the gnomAD database and has not been previously reported. Sequence analysis showed that the amino acid residue at position 184 is located within the Asp-Glu-Asp-Asp (DEDD) deadenylase domain, a mutation hotspot of TOE1. Conservation analysis indicates Arg 184 is highly conserved among various species.Moreover, analysis of the 3D structure revealed that this arginine to leucine mutation may disrupt the proper formation of the β-sheet in the secondary structure of TOE1 protein. VarCards predicted that the p.Arg184Leu variant would impair TOE1 function, according to SIFT (“Damaging”, score = 0.01), PolyPhen-2 (“Possibly damaging”, score = 0.89), MutationTaster (“Disease-causing”, score = 0.87), ClinPred (“Pathogenic”, score = 0.96), and CADD (“Damaging”, score = 24). According to the ACMG/AMP 2015 guideline (Richards et al., 2015), the c.551G>T, p.Arg184Leu variant was classified as likely pathogenic (PM1+ PM2+PM3+PP3).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Jun 23, 2024