VCV000002120.84 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(41)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

TSEN54:c.[277T>C;919G>T]

Identifiers

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

Variation ID: 2120 Accession: VCV000002120.84

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q25.1 17: 75522000 (GRCh38) [ NCBI UCSC ] 17: 73518081 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Nov 3, 2024	Oct 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_207346.3:c.919G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_997229.2:p.Ala307Ser	missense
NC_000017.11:g.75522000G>T
NC_000017.10:g.73518081G>T
NG_013041.1:g.10473G>T
	Q7Z6J9:p.Ala307Ser

... more HGVS ... less HGVS

Protein change

A307S

Other names

Canonical SPDI

NC_000017.11:75521999:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00090

Trans-Omics for Precision Medicine (TOPMed) 0.00091

The Genome Aggregation Database (gnomAD) 0.00092

Exome Aggregation Consortium (ExAC) 0.00123

Links

ClinGen: CA173740 Genetic Testing Registry (GTR): GTR000570417 UniProtKB: Q7Z6J9#VAR_054813 OMIM: 608755.0001 OMIM: 608755.0002 dbSNP: rs113994152 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TSEN54		-	-	GRCh38 GRCh37	587	659

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Pontocerebellar hypoplasia type 2A	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jun 5, 2024	RCV000002201.20
Olivopontocerebellar hypoplasia	Pathogenic (1)	criteria provided, single submitter	Feb 25, 2014	RCV000147790.8
Pontocerebellar hypoplasia type 4	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Apr 20, 2022	RCV000157630.14
Pontocerebellar hypoplasia type 5	Pathogenic (2)	criteria provided, single submitter	Jan 1, 2016	RCV000157631.9
not provided	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV000224437.51
Congenital cerebellar hypoplasia	Pathogenic (1)	criteria provided, single submitter	Jun 6, 2014	RCV000415005.5
Pontocerebellar hypoplasia type 2A Pontocerebellar hypoplasia type 4	Pathogenic (1)	criteria provided, single submitter	Sep 1, 2017	RCV000515314.7
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Mar 19, 2021	RCV000623727.8
Intellectual disability	Pathogenic (1)	criteria provided, single submitter	Aug 3, 2020	RCV001255369.4
Pontoneocerebellar hypoplasia	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 8, 2019	RCV001193388.9
Pontocerebellar hypoplasia type 2A Pontocerebellar hypoplasia type 4 Pontocerebellar hypoplasia type 5	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 18, 2024	RCV001813937.9
Methylmalonic aciduria and homocystinuria type cblD Pontocerebellar hypoplasia type 4 Pontocerebellar hypoplasia type 5	Pathogenic (1)	criteria provided, single submitter	Sep 4, 2019	RCV003153294.4
TSEN54 Pontocerebellar Hypoplasia	Pathogenic (1)	criteria provided, single submitter	-	RCV003335010.1
Global developmental delay Microcephaly	Pathogenic (1)	criteria provided, single submitter	Sep 10, 2015	RCV000414963.5
Amblyopia Global developmental delay Hypertonia	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000627018.5
Pontocerebellar hypoplasia type 2 Pontocerebellar hypoplasia type 4	not provided (1)	no classification provided	-	RCV001824557.5
TSEN54-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 24, 2024	RCV004755700.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 25, 2014)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	olivopontocerebellar hypoplasia (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000195261.1 First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014
Pathogenic (Sep 10, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Global developmental delay Microcephaly Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492810.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Jun 06, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebellar hypoplasia Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492959.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Jan 27, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000280756.2 First in ClinVar: Jun 08, 2016 Last updated: Mar 08, 2017
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Amblyopia Global developmental delay Hypertonia Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747721.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (Nov 29, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000232822.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 18711368‚ 20952379 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSEN54 Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Mar 28, 2017)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Pontoneocerebellar hypoplasia (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000712809.2 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (12) PubMed: 27430971‚ 26701950‚ 21468723‚ 21609947‚ 19459882‚ 27570394‚ 20956791‚ 18711368‚ 24886362‚ 23177318‚ 23307886‚ 20803644 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (Nov 08, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Pontoneocerebellar hypoplasia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001362173.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (1) PubMed: 20952379 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 5 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001370382.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. This variant was detected in homozygous state.
Pathogenic (Apr 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Pontocerebellar hypoplasia type 4 Affected status: yes Allele origin: maternal	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: HudsonAlpha-AGHI-WGS Accession: SCV002515837.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG codes: PS4, PM2, PM3, PP1, PP3 Number of individuals with the variant: 1 Clinical Features: Microcephaly (present) , Seizure (present) , Global developmental delay (present) , Macrogyria (present) , Cerebellar hypoplasia (present) , Lissencephaly (present) , Hip dislocation (present) , … (more) Microcephaly (present) , Seizure (present) , Global developmental delay (present) , Macrogyria (present) , Cerebellar hypoplasia (present) , Lissencephaly (present) , Hip dislocation (present) , Feeding difficulties (present) , Cerebral palsy (present) (less)
Pathogenic (Nov 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022449.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002237126.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 18711368‚ 24886362‚ 26701950‚ 27430971 Comment: This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the TSEN54 protein (p.Ala307Ser). … (more) This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the TSEN54 protein (p.Ala307Ser). This variant is present in population databases (rs113994152, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with pontocerebellar hypoplasia (PMID: 18711368, 24886362, 26701950, 27430971). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2120). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSEN54 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 2A Affected status: no Allele origin: germline	Institute of Immunology and Genetics Kaiserslautern Accession: SCV004803195.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Comment: ACMG Criteria: PS3, PS4, PM3, PP1, PP5, Variant was found in heterozygous state
Pathogenic (Dec 03, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Pontocerebellar hypoplasia type 2A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001164440.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Publications: PubMed (7) PubMed: 23307886‚ 21368912‚ 29410950‚ 20803644‚ 27570394‚ 18711368‚ 24886362 Comment: The homozygous p.Ala307Ser variant in TSEN54 was identified by our study in two siblings with pontocerebellar hypoplasia. This variant has been identified in 0.09241% (216/233752) … (more) The homozygous p.Ala307Ser variant in TSEN54 was identified by our study in two siblings with pontocerebellar hypoplasia. This variant has been identified in 0.09241% (216/233752) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs113994152). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservational analyses do not provide strong support for or against an impact to the protein. The p.Ala307Ser variant in TSEN54 has been reported in 88 homozygous or heterozygous individuals with pontocerebellar hypoplasia, segregated with disease in 20 affected relatives from 10 families, and is believed to be a founder variant from the Netherlands (PMID: 23307886, 21368912, 29410950, 20803644, 27570394, 18711368, 24886362). The presence of this variant in combination with loss of function and missense variants (reported pathogenic in the literature) and in 8 individuals with pontocerebellar hypoplasia, included in the 88 individuals mentioned earlier, increases the likelihood that the p.Ala307Ser variant is pathogenic. This variant has also been reported pathogenic by multiple submitters in ClinVar (Variation ID: 2120). In summary, the p.Ala307Ser variant is pathogenic based off of our findings and multiple reports in ClinVar. ACMG/AMP Criteria applied: PM2, PM3_Strong, PP1_Strong (Richards 2015). (less)
Pathogenic (Aug 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability Affected status: yes Allele origin: biparental	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001431699.1 First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020	Comment: The variant c.919G>T, p.(Ala307Ser) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant … (more) The variant c.919G>T, p.(Ala307Ser) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was M + P.The variant likely explains the NDD in this individual. (less)
Pathogenic (Jun 19, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 4 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001522394.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Jan 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 4 Affected status: yes Allele origin: biparental	Provincial Medical Genetics Program of British Columbia, University of British Columbia Accession: SCV002320817.1 First in ClinVar: Apr 11, 2022 Last updated: Apr 11, 2022	Sex: male
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 2A Affected status: yes Allele origin: germline	3billion Accession: SCV002573333.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (9) PubMed: 27430971‚ 20952379‚ 29410950‚ 20803644‚ 18711368‚ 26701950‚ 20956791‚ 21609947‚ 24886362 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.088%). The variant has been previously reported as … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.088%). The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002120). The variant has been observed in multiple (>3) similarly affected unrelated individuals, and reported to be homozygous in at least two similarly affected unrelated individuals (PMID: 24886362 , 26701950 , 27430971 , 29410950). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 18711368 , 20803644 , 29410950). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Global developmental delay (present) , Poor suck (present) , Severe failure to thrive (present) , Motor delay (present) , Hypotonia (present) , Upper limb spasticity … (more) Global developmental delay (present) , Poor suck (present) , Severe failure to thrive (present) , Motor delay (present) , Hypotonia (present) , Upper limb spasticity (present) , Cerebellar hypoplasia (present) , Corpus callosum, agenesis of (present) , Microcephaly (present) (less)
Pathogenic (Feb 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 2A Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581280.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PM3_VSTR, PS4, PP1_STR, PM2_SUP	Number of individuals with the variant: 6 Sex: female
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 2A Pontocerebellar hypoplasia type 4 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Baylor Genetics Accession: SCV000807649.2 First in ClinVar: Nov 11, 2017 Last updated: Dec 11, 2022	Publications: PubMed (4) PubMed: 25326635‚ 18711368‚ 23177318‚ 24886362 Comment: This variant has been previously reported as disease-causing and was found six times in our laboratory, either homozygous or compound heterozygous, in individuals with pontocerebellar … (more) This variant has been previously reported as disease-causing and was found six times in our laboratory, either homozygous or compound heterozygous, in individuals with pontocerebellar hypoplasia. Heterozygotes would be expected to be asymptomatic carriers. (less)
Pathogenic (Dec 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 4 Pontocerebellar hypoplasia type 2A Pontocerebellar hypoplasia type 5 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611245.2 First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022
Pathogenic (Dec 18, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321984.9 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. … (more) In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30525188, 32360255, 24886362, 23177318, 26701950, 20952379, 18711368, 23307886, 27430971, 29410950, 29286531, 30792901, 31623504, 32404165, 30609409, 34426522, 31589614, 32629522, 31319225) (less)
Pathogenic (Sep 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 5 Methylmalonic aciduria and homocystinuria type cblD Pontocerebellar hypoplasia type 4 (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV003843206.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: This variant was observed in compound heterozygosity with variant c.953del Method: Exome sequencing
Pathogenic (Jun 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 2A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004040971.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	TSEN54 Pontocerebellar Hypoplasia Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046028.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This variant has been reported in over 100 affected individuals as a homozygous or compound heterozygous change in patients with pontocerebellar hypoplasia and has been … (more) This variant has been reported in over 100 affected individuals as a homozygous or compound heterozygous change in patients with pontocerebellar hypoplasia and has been identified in 90% of individuals with pontocerebellar hypoplasia type 2 (PCH2, PMID: 24886362, 20301773). This variant has been shown to segregate with disease in more than 20 affected relatives from 10 families (PMID: 23307886, 21368912, 29410950, 20803644, 20956791, 23177318, 21468723, 21609947, 26701950, 27570394, 18711368, 24886362). Additionally, the c.919G>T (p.Ala307Ser) variant is a common homozygous missense variant that has been identified in 33 individuals, from nonconsanguineous families, who all survived until 11 years of age (PMID: 24886362). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.089% (213/240704) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.919G>T (p.Ala307Ser) variant on protein function. Based on the available evidence, the c.919G>T (p.Ala307Ser) variant is classified as Pathogenic. (less)
Pathogenic (Dec 19, 2018)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Pontoneocerebellar hypoplasia Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004801533.1 First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024	Comment: 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). … (more) 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. (less)
Pathogenic (Mar 19, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000741184.6 First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 16470708‚ 18711368‚ 20952379‚ 20956791‚ 21368912 Comment: The c.919G>T (p.A307S) alteration is located in coding exon 8 of the TSEN54 gene. This alteration results from a G to T substitution at nucleotide … (more) The c.919G>T (p.A307S) alteration is located in coding exon 8 of the TSEN54 gene. This alteration results from a G to T substitution at nucleotide position 919, causing the alanine (A) at amino acid position 307 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.088% (213/240704) total alleles studied. The highest observed frequency was 0.173% (183/105724) of European (non-Finnish) alleles. This mutation is the most common variant causing TSEN54-related pontocerebellar hypoplasia, found in more than 90% of patients (Budde, 2008; Cassandrini, 2010; Namavar, 2011). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jun 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 2A (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428941.3 First in ClinVar: Aug 15, 2020 Last updated: Oct 13, 2024	Comment: Criteria applied: PM3_VSTR,PP1_STR,PM2_SUP,PP3 Clinical Features: Hypopnea (present) , Cerebellar hypoplasia (present) , Olivopontocerebellar hypoplasia (present) Sex: female
Pathogenic (Oct 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249377.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Comment: TSEN54: PM3:Very Strong, PP1:Strong, PM2:Supporting Number of individuals with the variant: 13
Pathogenic (Oct 18, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 5 Pontocerebellar hypoplasia type 2A Pontocerebellar hypoplasia type 4 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002061384.3 First in ClinVar: Jan 22, 2022 Last updated: Nov 03, 2024	Comment: PM3_Very Strong, PP1_Strong
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001742679.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958291.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Jun 01, 2011)	no assertion criteria provided Method: literature only	PONTOCEREBELLAR HYPOPLASIA, TYPE 2A Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022359.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 17, 2024	Publications: PubMed (3) PubMed: 18711368‚ 20956791‚ 21368912 Comment on evidence: In 42 individuals with pontocerebellar hypoplasia type 2 (PCH2A; 277470), Budde et al. (2008) identified homozygosity for a 919G-T transversion in the TSEN54 gene, resulting … (more) In 42 individuals with pontocerebellar hypoplasia type 2 (PCH2A; 277470), Budde et al. (2008) identified homozygosity for a 919G-T transversion in the TSEN54 gene, resulting in an ala307-to-ser (A307S) substitution. This mutation is likely due to a single founder event estimated by Budde et al. (2008) to have occurred at least 11 to 16 generations ago. This region of the protein is conserved in mammals and chicken but is not highly conserved in lower organisms. Analysis of 451 Dutch and 279 German control DNA samples yielded no homozygous and only 5 Dutch and 1 German heterozygous genotypes. Additionally, Budde et al. (2008) screened 136 healthy unrelated individuals from Volendam; no homozygous individuals and only 2 heterozygous individuals were identified. Thus, the allele frequency of the 919G-T variant in the PCH2 subjects was 0.884, counting the Volendam subjects as a single data point, and that in the control population was 0.004. These data strongly suggested that the TSEN54 locus is responsible for most cases of PCH2. Budde et al. (2008) also found the 919G-T mutation in 3 individuals with pontocerebellar hypoplasia type 4 (PCH4; 225753), in isolation on 3 alleles (with compound heterozygosity in 2; see 608755.0003, 608755.0004) and once in a complex mutation with another missense substitution (608755.0002). Cassandrini et al. (2010) identified a homozygous A307S mutation in 7 affected individuals from 6 unrelated Italian families with PCH2A. Two additional patients had a heterozygous A307S mutation: 1 patient with a PCH2A phenotype in whom the second mutation could not be detected, and another patient with a more severe phenotype (PCH4) who was compound heterozygous for A307S and a truncating mutation (608755.0005). Thus, A307S accounted for 16 (89%) of 18 mutant alleles, and haplotype analysis suggested a founder effect. In a patient with pontocerebellar hypoplasia type 5 (PCH5; 610204), Namavar et al. (2011) identified compound heterozygosity for the common A307S mutation and a splice site mutation (608755.0006). (less)
Likely pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Pontocerebellar hypoplasia type 4 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760410.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808561.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001972364.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Jun 01, 2011)	no assertion criteria provided Method: literature only	PONTOCEREBELLAR HYPOPLASIA, TYPE 5 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000207438.2 First in ClinVar: Feb 13, 2015 Last updated: Jun 17, 2024	Publications: PubMed (3) PubMed: 18711368‚ 20956791‚ 21368912 Comment on evidence: In 42 individuals with pontocerebellar hypoplasia type 2 (PCH2A; 277470), Budde et al. (2008) identified homozygosity for a 919G-T transversion in the TSEN54 gene, resulting … (more) In 42 individuals with pontocerebellar hypoplasia type 2 (PCH2A; 277470), Budde et al. (2008) identified homozygosity for a 919G-T transversion in the TSEN54 gene, resulting in an ala307-to-ser (A307S) substitution. This mutation is likely due to a single founder event estimated by Budde et al. (2008) to have occurred at least 11 to 16 generations ago. This region of the protein is conserved in mammals and chicken but is not highly conserved in lower organisms. Analysis of 451 Dutch and 279 German control DNA samples yielded no homozygous and only 5 Dutch and 1 German heterozygous genotypes. Additionally, Budde et al. (2008) screened 136 healthy unrelated individuals from Volendam; no homozygous individuals and only 2 heterozygous individuals were identified. Thus, the allele frequency of the 919G-T variant in the PCH2 subjects was 0.884, counting the Volendam subjects as a single data point, and that in the control population was 0.004. These data strongly suggested that the TSEN54 locus is responsible for most cases of PCH2. Budde et al. (2008) also found the 919G-T mutation in 3 individuals with pontocerebellar hypoplasia type 4 (PCH4; 225753), in isolation on 3 alleles (with compound heterozygosity in 2; see 608755.0003, 608755.0004) and once in a complex mutation with another missense substitution (608755.0002). Cassandrini et al. (2010) identified a homozygous A307S mutation in 7 affected individuals from 6 unrelated Italian families with PCH2A. Two additional patients had a heterozygous A307S mutation: 1 patient with a PCH2A phenotype in whom the second mutation could not be detected, and another patient with a more severe phenotype (PCH4) who was compound heterozygous for A307S and a truncating mutation (608755.0005). Thus, A307S accounted for 16 (89%) of 18 mutant alleles, and haplotype analysis suggested a founder effect. In a patient with pontocerebellar hypoplasia type 5 (PCH5; 610204), Namavar et al. (2011) identified compound heterozygosity for the common A307S mutation and a splice site mutation (608755.0006). (less)
Pathogenic (Jun 01, 2011)	no assertion criteria provided Method: literature only	PONTOCEREBELLAR HYPOPLASIA, TYPE 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000207437.2 First in ClinVar: Feb 13, 2015 Last updated: Jun 17, 2024	Publications: PubMed (3) PubMed: 18711368‚ 20956791‚ 21368912 Comment on evidence: In 42 individuals with pontocerebellar hypoplasia type 2 (PCH2A; 277470), Budde et al. (2008) identified homozygosity for a 919G-T transversion in the TSEN54 gene, resulting … (more) In 42 individuals with pontocerebellar hypoplasia type 2 (PCH2A; 277470), Budde et al. (2008) identified homozygosity for a 919G-T transversion in the TSEN54 gene, resulting in an ala307-to-ser (A307S) substitution. This mutation is likely due to a single founder event estimated by Budde et al. (2008) to have occurred at least 11 to 16 generations ago. This region of the protein is conserved in mammals and chicken but is not highly conserved in lower organisms. Analysis of 451 Dutch and 279 German control DNA samples yielded no homozygous and only 5 Dutch and 1 German heterozygous genotypes. Additionally, Budde et al. (2008) screened 136 healthy unrelated individuals from Volendam; no homozygous individuals and only 2 heterozygous individuals were identified. Thus, the allele frequency of the 919G-T variant in the PCH2 subjects was 0.884, counting the Volendam subjects as a single data point, and that in the control population was 0.004. These data strongly suggested that the TSEN54 locus is responsible for most cases of PCH2. Budde et al. (2008) also found the 919G-T mutation in 3 individuals with pontocerebellar hypoplasia type 4 (PCH4; 225753), in isolation on 3 alleles (with compound heterozygosity in 2; see 608755.0003, 608755.0004) and once in a complex mutation with another missense substitution (608755.0002). Cassandrini et al. (2010) identified a homozygous A307S mutation in 7 affected individuals from 6 unrelated Italian families with PCH2A. Two additional patients had a heterozygous A307S mutation: 1 patient with a PCH2A phenotype in whom the second mutation could not be detected, and another patient with a more severe phenotype (PCH4) who was compound heterozygous for A307S and a truncating mutation (608755.0005). Thus, A307S accounted for 16 (89%) of 18 mutant alleles, and haplotype analysis suggested a founder effect. In a patient with pontocerebellar hypoplasia type 5 (PCH5; 610204), Namavar et al. (2011) identified compound heterozygosity for the common A307S mutation and a splice site mutation (608755.0006). (less)
Pathogenic (Mar 24, 2024)	no assertion criteria provided Method: clinical testing	TSEN54-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005350713.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The TSEN54 c.919G>T variant is predicted to result in the amino acid substitution p.Ala307Ser. This variant is the most common cause of autosomal recessive pontocerebellar … (more) The TSEN54 c.919G>T variant is predicted to result in the amino acid substitution p.Ala307Ser. This variant is the most common cause of autosomal recessive pontocerebellar hypoplasia type 2A (Sánchez-Albisua et al. 2014. PubMed ID: 24886362; Budde et al. 2008. PubMed ID: 18711368). This variant is interpreted as pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Pontocerebellar hypoplasia type 2A Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000041744.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301773 BookShelf: NBK9673 BookShelf: NBK9673
not provided (-)	no classification provided Method: phenotyping only	Pontocerebellar hypoplasia type 4 Pontocerebellar hypoplasia type 2 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline, paternal	GenomeConnect, ClinGen Accession: SCV002074991.2 First in ClinVar: Feb 12, 2022 Last updated: Jun 17, 2024	Comment: Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported, most recently, on 08-21-2020 by Lab or GTR ID 26957. GenomeConnect assertions are … (more) Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported, most recently, on 08-21-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Hypertonia (present) , Umbilical hernia (present) , Microcephaly (present) , Posterior fossa cyst (present) Indication for testing: Diagnostic Age: 0-9 years Sex: male Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2020-07-24 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Abnormal delivery (present) , Pregnancy history (present) , Failure to thrive (present) , Ptosis (present) , Hypertonia (present) , Generalized hypotonia (present) Indication for testing: Diagnostic Age: 0-9 years Sex: male Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2020-08-21 Testing laboratory interpretation: Pathogenic
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Comment:

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.

Comment:

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.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the TSEN54 protein (p.Ala307Ser). This variant is present in population databases (rs113994152, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with pontocerebellar hypoplasia (PMID: 18711368, 24886362, 26701950, 27430971). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2120). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSEN54 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The homozygous p.Ala307Ser variant in TSEN54 was identified by our study in two siblings with pontocerebellar hypoplasia. This variant has been identified in 0.09241% (216/233752) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs113994152). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservational analyses do not provide strong support for or against an impact to the protein. The p.Ala307Ser variant in TSEN54 has been reported in 88 homozygous or heterozygous individuals with pontocerebellar hypoplasia, segregated with disease in 20 affected relatives from 10 families, and is believed to be a founder variant from the Netherlands (PMID: 23307886, 21368912, 29410950, 20803644, 27570394, 18711368, 24886362). The presence of this variant in combination with loss of function and missense variants (reported pathogenic in the literature) and in 8 individuals with pontocerebellar hypoplasia, included in the 88 individuals mentioned earlier, increases the likelihood that the p.Ala307Ser variant is pathogenic. This variant has also been reported pathogenic by multiple submitters in ClinVar (Variation ID: 2120). In summary, the p.Ala307Ser variant is pathogenic based off of our findings and multiple reports in ClinVar. ACMG/AMP Criteria applied: PM2, PM3_Strong, PP1_Strong (Richards 2015).

Comment:

The variant c.919G>T, p.(Ala307Ser) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was M + P.The variant likely explains the NDD in this individual.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.088%). The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002120). The variant has been observed in multiple (>3) similarly affected unrelated individuals, and reported to be homozygous in at least two similarly affected unrelated individuals (PMID: 24886362 , 26701950 , 27430971 , 29410950). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 18711368 , 20803644 , 29410950). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This variant has been previously reported as disease-causing and was found six times in our laboratory, either homozygous or compound heterozygous, in individuals with pontocerebellar hypoplasia. Heterozygotes would be expected to be asymptomatic carriers.

Comment:

In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30525188, 32360255, 24886362, 23177318, 26701950, 20952379, 18711368, 23307886, 27430971, 29410950, 29286531, 30792901, 31623504, 32404165, 30609409, 34426522, 31589614, 32629522, 31319225)

Comment:

This variant has been reported in over 100 affected individuals as a homozygous or compound heterozygous change in patients with pontocerebellar hypoplasia and has been identified in 90% of individuals with pontocerebellar hypoplasia type 2 (PCH2, PMID: 24886362, 20301773). This variant has been shown to segregate with disease in more than 20 affected relatives from 10 families (PMID: 23307886, 21368912, 29410950, 20803644, 20956791, 23177318, 21468723, 21609947, 26701950, 27570394, 18711368, 24886362). Additionally, the c.919G>T (p.Ala307Ser) variant is a common homozygous missense variant that has been identified in 33 individuals, from nonconsanguineous families, who all survived until 11 years of age (PMID: 24886362). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.089% (213/240704) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.919G>T (p.Ala307Ser) variant on protein function. Based on the available evidence, the c.919G>T (p.Ala307Ser) variant is classified as Pathogenic.

Comment:

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.

Comment:

The c.919G>T (p.A307S) alteration is located in coding exon 8 of the TSEN54 gene. This alteration results from a G to T substitution at nucleotide position 919, causing the alanine (A) at amino acid position 307 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.088% (213/240704) total alleles studied. The highest observed frequency was 0.173% (183/105724) of European (non-Finnish) alleles. This mutation is the most common variant causing TSEN54-related pontocerebellar hypoplasia, found in more than 90% of patients (Budde, 2008; Cassandrini, 2010; Namavar, 2011). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The TSEN54 c.919G>T variant is predicted to result in the amino acid substitution p.Ala307Ser. This variant is the most common cause of autosomal recessive pontocerebellar hypoplasia type 2A (Sánchez-Albisua et al. 2014. PubMed ID: 24886362; Budde et al. 2008. PubMed ID: 18711368). This variant is interpreted as pathogenic.

Comment:

Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported, most recently, on 08-21-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
TSEN54 Pontocerebellar Hypoplasia.	Adam MP	-	2020	PMID: 20301773
TSEN54 Gene-Related Pontocerebellar Hypoplasia Type 2 Could Mimic Dyskinetic Cerebral Palsy with Severe Psychomotor Retardation.	Pacheva IH	Frontiers in pediatrics	2018	PMID: 29410950
Intractable epileptic spasms in a patient with Pontocerebellar hypoplasia: Severe phenotype of type 2 or another subtype?	Samanta D	Annals of Indian Academy of Neurology	2016	PMID: 27570394
Brain morphometry in Pontocerebellar Hypoplasia type 2.	Ekert K	Orphanet journal of rare diseases	2016	PMID: 27430971
TSEN54 gene-related pontocerebellar hypoplasia type 2 presenting with exaggerated startle response: report of two cases in a family.	Maraş-Genç H	The Turkish journal of pediatrics	2015	PMID: 26701950
Natural course of pontocerebellar hypoplasia type 2A.	Sánchez-Albisua I	Orphanet journal of rare diseases	2014	PMID: 24886362
Novel mutations in TSEN54 in pontocerebellar hypoplasia type 2.	Battini R	Journal of child neurology	2014	PMID: 23307886
Recurrent episodes of rhabdomyolysis in pontocerebellar hypoplasia type 2.	Zafeiriou DI	Neuromuscular disorders : NMD	2013	PMID: 23177318
Mutations of TSEN and CASK genes are prevalent in pontocerebellar hypoplasias type 2 and 4.	Valayannopoulos V	Brain : a journal of neurology	2012	PMID: 21609947
TSEN54 mutation in a child with pontocerebellar hypoplasia type 1.	Simonati A	Acta neuropathologica	2011	PMID: 21468723
TSEN54 mutations cause pontocerebellar hypoplasia type 5.	Namavar Y	European journal of human genetics : EJHG	2011	PMID: 21368912
Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia.	Namavar Y	Brain : a journal of neurology	2011	PMID: 20952379
Pontocerebellar hypoplasia: clinical, pathologic, and genetic studies.	Cassandrini D	Neurology	2010	PMID: 20956791
Molecular and neuroimaging findings in pontocerebellar hypoplasia type 2 (PCH2): is prenatal diagnosis possible?	Graham JM Jr	American journal of medical genetics. Part A	2010	PMID: 20803644
Mutations in the tRNA splicing endonuclease complex cause pontocerebellar hypoplasia.	Bailey KA	Clinical genetics	2009	PMID: 19459882
tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia.	Budde BS	Nature genetics	2008	PMID: 18711368
Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5?	Patel MS	American journal of medical genetics. Part A	2006	PMID: 16470708
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSEN54	-	-	-	-
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Text-mined citations for rs113994152 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs113994152 ...