NM_052965.4(TSEN15):c.346C>T (p.His116Tyr) AND Pontocerebellar hypoplasia, type 2F

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 1, 2020
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:: RCV000234984.4

Allele description [Variation Report for NM_052965.4(TSEN15):c.346C>T (p.His116Tyr)]

NM_052965.4(TSEN15):c.346C>T (p.His116Tyr)

Gene:

TSEN15:tRNA splicing endonuclease subunit 15 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q25.3

Genomic location:

Preferred name:

NM_052965.4(TSEN15):c.346C>T (p.His116Tyr)

HGVS:

NC_000001.11:g.184054856C>T
NG_050569.1:g.8206C>T
NM_001127394.4:c.346C>T
NM_001300764.2:c.346C>T
NM_001300766.2:c.346C>T
NM_001363643.2:c.346C>T
NM_052965.4:c.346C>TMANE SELECT
NP_001120866.1:p.His116Tyr
NP_001287693.1:p.His116Tyr
NP_001287695.1:p.His116Tyr
NP_001350572.1:p.His116Tyr
NP_443197.1:p.His116Tyr
NC_000001.10:g.184023990C>T
NM_001127394.2:c.346C>T
NM_052965.3:c.346C>T
NR_023349.3:n.372C>T
NR_125335.2:n.372C>T
Q8WW01:p.His116Tyr

Protein change:

H116Y; HIS116TYR

Links:

UniProtKB: Q8WW01#VAR_077062; OMIM: 608756.0003; dbSNP: rs879253780

NCBI 1000 Genomes Browser:

rs879253780

Molecular consequence:

NM_001127394.4:c.346C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001300764.2:c.346C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001300766.2:c.346C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363643.2:c.346C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_052965.4:c.346C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_023349.3:n.372C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_125335.2:n.372C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Pontocerebellar hypoplasia, type 2F
Identifiers:: MONDO: MONDO:0014874; MedGen: C4310757; Orphanet: 2524; OMIM: 617026

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000292332	OMIM	no assertion criteria provided	Pathogenic (Sep 26, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001443028	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2020)	biparental	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000292332

OMIM

no assertion criteria provided

Pathogenic
(Sep 26, 2016)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV001443028

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 1, 2020)

biparental

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	biparental	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Autosomal-Recessive Mutations in the tRNA Splicing Endonuclease Subunit TSEN15 Cause Pontocerebellar Hypoplasia and Progressive Microcephaly.

Breuss MW, Sultan T, James KN, Rosti RO, Scott E, Musaev D, Furia B, Reis A, Sticht H, Al-Owain M, Alkuraya FS, Reuter MS, Abou Jamra R, Trotta CR, Gleeson JG.

Am J Hum Genet. 2016 Jul 7;99(1):228-35. doi: 10.1016/j.ajhg.2016.05.023. Erratum in: Am J Hum Genet. 2016 Sep 1;99(3):785. doi: 10.1016/j.ajhg.2016.08.009.

PubMed [citation]

PMID:: 27392077
PMCID:: PMC5005448

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 OMIM, SCV000292332.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 brothers, born of consanguineous Syrian parents, with pontocerebellar hypoplasia type 2F (PCH2F; 617016), Breuss et al. (2016) identified a homozygous c.346C-T transition (c.346C-T, NM_052965.3) in exon 3 of the TSEN15 gene, resulting in a his116-to-tyr (H116Y) substitution at a highly conserved residue on the surface of the protein in an area that is putatively involved in TSEN34 (608754) interaction. The mutation, which was found by direct sequencing, segregated with the disorder in the family. Cells transfected with the mutation showed normal levels of the mutant protein, but decreased association with other TSEN subunits compared to controls. In vitro functional expression assay showed that the mutant protein had almost complete loss of enzymatic function with an absence of cleaved substrate.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001443028.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS3,PM2;PM3_Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	biparental	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 23, 2022

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