NM_207346.3(TSEN54):c.919G>T (p.Ala307Ser) AND Pontoneocerebellar hypoplasia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 8, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001193388.9

Allele description [Variation Report for NM_207346.3(TSEN54):c.919G>T (p.Ala307Ser)]

NM_207346.3(TSEN54):c.919G>T (p.Ala307Ser)

Gene:

TSEN54:tRNA splicing endonuclease subunit 54 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.1

Genomic location:

Preferred name:

NM_207346.3(TSEN54):c.919G>T (p.Ala307Ser)

HGVS:

NC_000017.11:g.75522000G>T
NG_013041.1:g.10473G>T
NM_207346.3:c.919G>TMANE SELECT
NP_997229.2:p.Ala307Ser
NC_000017.10:g.73518081G>T
NM_207346.2:c.919G>T
Q7Z6J9:p.Ala307Ser

Protein change:

A307S; ALA307SER

Links:

UniProtKB: Q7Z6J9#VAR_054813; OMIM: 608755.0001; OMIM: 608755.0002; dbSNP: rs113994152

NCBI 1000 Genomes Browser:

rs113994152

Molecular consequence:

NM_207346.3:c.919G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Pontoneocerebellar hypoplasia
Synonyms:: Pontocerebellar hypoplasia; Non-syndromic pontocerebellar hypoplasia
Identifiers:: MONDO: MONDO:0020135; MedGen: C1261175; Orphanet: 98523; OMIM: PS607596

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000712809	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 28, 2017)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 27430971, 26701950, 21468723, 21609947, 19459882, 27570394, 20956791, 18711368, 24886362, 23177318, 23307886, 20803644, 24033266
SCV001362173	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 8, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004801533	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Dec 19, 2018)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000712809

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Mar 28, 2017)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV001362173

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 8, 2019)

germline

clinical testing

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

Citation Link,

SCV004801533

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Pathogenic
(Dec 19, 2018)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Brain morphometry in Pontocerebellar Hypoplasia type 2.

Ekert K, Groeschel S, Sánchez-Albisua I, Frölich S, Dieckmann A, Engel C, Krägeloh-Mann I.

Orphanet J Rare Dis. 2016 Jul 19;11(1):100. doi: 10.1186/s13023-016-0481-4.

PubMed [citation]

PMID:: 27430971
PMCID:: PMC4950429

Maraş-Genç H, Uyur-Yalçın E, Rosti RÖ, Gleeson JG, Kara B.

Turk J Pediatr. 2015 May-Jun;57(3):286-9.

PubMed [citation]

PMID:: 26701950
PMCID:: PMC4991034

See all PubMed Citations (14)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712809.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (13)

Description

The p.Ala307Ser (NM_207346.2 c.919G>T) variant in TSEN54 has been reported in gr eater than 30 homozygous or compound heterozygous individuals with pontocerebell ar hypoplasia and segregated in several affected family members (Budde 2008, Cas sandrini 2010, Graham 2010, Simonati 2011, Valayannopoulos 2012, Zafeiriou 2013, Sanchez-Albisua 2014, Battini 2014, Maras-Genc 2015, and Samanta 2016). This va riant has been identified in 69/33,364 of European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs113994152). Al though this variant has been seen in the general population, its frequency is lo w enough to be consistent with a recessive carrier frequency. In summary, this v ariant meets criteria to be classified as pathogenic for pontocerebellar hypopla sia in an autosomal recessive manner based upon its biallelic occurrence in pati ents and segregation in affected family members.

#	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		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362173.1

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

Description

Variant summary: TSEN54 c.919G>T (p.Ala307Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0009 in 209398 control chromosomes (gnomAD). c.919G>T has been reported in the literature in multiple individuals affected with Pontocerebellar hypoplasia (e.g. Namavar_2011). These data indicate that the variant is very likely to be associated with disease. GeneReviews indicates the variant to be a common disease variant. Eight ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

From Illumina Laboratory Services, Illumina, SCV004801533.1

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

Description

The TSEN54 c.919G>T (p.Ala307Ser) variant is well-described in the literature as the most common pathogenic variant in individuals with varied subtypes of pontocerebellar hypoplasia (PCH). The p.Ala307Ser variant is reported in three studies and was found in a total of 57 patients, including 45 patients in a homozygous state, three in a compound heterozygous state and nine in a heterozygous state (Budde et al. 2008; Cassandrini et al. 2010; Namavar et al. 2011). Segregation of the variant with the disease in a recessive manner was shown in a large family (Budde et al. 2008). The p.Ala307Ser variant was absent from 724/730 controls, and is reported at a frequency of 0.00173 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Ala307Ser variant is classified as pathogenic for pontocerebellar hypoplasia.

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

Last Updated: Nov 10, 2024

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