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

gnomAD frequency: 0.00092  dbSNP: rs113994152

Total submissions: 41

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147790	SCV000195261	pathogenic	Olivopontocerebellar hypoplasia	2014-02-25	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000224437	SCV000232822	pathogenic	not provided	2017-11-29	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224437	SCV000280756	pathogenic	not provided	2017-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000224437	SCV000321984	pathogenic	not provided	2020-12-18	criteria provided, single submitter	clinical testing	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)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414963	SCV000492810	pathogenic	Global developmental delay; Microcephaly	2015-09-10	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415005	SCV000492959	pathogenic	Congenital cerebellar hypoplasia	2014-06-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001813937	SCV000611245	pathogenic	Pontocerebellar hypoplasia type 4; Pontocerebellar hypoplasia type 2A; Pontocerebellar hypoplasia type 5	2024-03-08	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001193388	SCV000712809	pathogenic	Pontoneocerebellar hypoplasia	2017-03-28	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000623727	SCV000741184	pathogenic	Inborn genetic diseases	2021-03-19	criteria provided, single submitter	clinical testing	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000627018	SCV000747721	pathogenic	Global developmental delay; Hypertonia; Amblyopia	2017-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000515314	SCV000807649	pathogenic	Pontocerebellar hypoplasia type 4; Pontocerebellar hypoplasia type 2A	2017-09-01	criteria provided, single submitter	clinical testing	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000002201	SCV001164440	pathogenic	Pontocerebellar hypoplasia type 2A	2018-12-03	criteria provided, single submitter	research	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).
CeGaT Center for Human Genetics Tuebingen	RCV000224437	SCV001249377	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	TSEN54: PM3:Very Strong, PM2, PP1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193388	SCV001362173	pathogenic	Pontoneocerebellar hypoplasia	2019-11-08	criteria provided, single submitter	clinical testing	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000157631	SCV001370382	pathogenic	Pontocerebellar hypoplasia type 5	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. This variant was detected in homozygous state.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000002201	SCV001428941	pathogenic	Pontocerebellar hypoplasia type 2A	2024-06-05	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PP1_STR,PM2_SUP,PP3
Institute of Human Genetics, University of Leipzig Medical Center	RCV001255369	SCV001431699	pathogenic	Intellectual disability	2020-08-03	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000157630	SCV001522394	pathogenic	Pontocerebellar hypoplasia type 4	2020-06-19	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000224437	SCV002022449	pathogenic	not provided	2021-11-29	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001813937	SCV002061384	pathogenic	Pontocerebellar hypoplasia type 4; Pontocerebellar hypoplasia type 2A; Pontocerebellar hypoplasia type 5	2024-10-18	criteria provided, single submitter	clinical testing	PM3_Very Strong, PP1_Strong
Labcorp Genetics (formerly Invitae), Labcorp	RCV000224437	SCV002237126	pathogenic	not provided	2025-01-23	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSEN54 protein function. 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.
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000157630	SCV002320817	pathogenic	Pontocerebellar hypoplasia type 4	2022-01-01	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000157630	SCV002515837	pathogenic	Pontocerebellar hypoplasia type 4	2022-04-20	criteria provided, single submitter	research	ACMG codes: PS4, PM2, PM3, PP1, PP3
3billion, Medical Genetics	RCV000002201	SCV002573333	pathogenic	Pontocerebellar hypoplasia type 2A	2022-09-01	criteria provided, single submitter	clinical testing	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.
MGZ Medical Genetics Center	RCV000002201	SCV002581280	pathogenic	Pontocerebellar hypoplasia type 2A	2022-02-23	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV003153294	SCV003843206	pathogenic	Methylmalonic aciduria and homocystinuria type cblD; Pontocerebellar hypoplasia type 4; Pontocerebellar hypoplasia type 5	2019-09-04	criteria provided, single submitter	clinical testing	This variant was observed in compound heterozygosity with variant c.953del
Baylor Genetics	RCV000002201	SCV004040971	pathogenic	Pontocerebellar hypoplasia type 2A	2023-06-30	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335010	SCV004046028	pathogenic	TSEN54 Pontocerebellar Hypoplasia		criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001193388	SCV004801533	pathogenic	Pontoneocerebellar hypoplasia	2018-12-19	criteria provided, single submitter	clinical testing	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.
Institute of Immunology and Genetics Kaiserslautern	RCV000002201	SCV004803195	pathogenic	Pontocerebellar hypoplasia type 2A	2024-02-16	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PS4, PM3, PP1, PP5, Variant was found in heterozygous state
OMIM	RCV000002201	SCV000022359	pathogenic	Pontocerebellar hypoplasia type 2A	2011-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000002201	SCV000041744	not provided	Pontocerebellar hypoplasia type 2A		no assertion provided	literature only
OMIM	RCV000157630	SCV000207437	pathogenic	Pontocerebellar hypoplasia type 4	2011-06-01	no assertion criteria provided	literature only
OMIM	RCV000157631	SCV000207438	pathogenic	Pontocerebellar hypoplasia type 5	2011-06-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224437	SCV001742679	pathogenic	not provided		no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000157630	SCV001760410	likely pathogenic	Pontocerebellar hypoplasia type 4		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000224437	SCV001808561	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000224437	SCV001958291	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224437	SCV001972364	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001824557	SCV002074991	not provided	Pontocerebellar hypoplasia type 4; Pontocerebellar hypoplasia type 2		no assertion provided	phenotyping only	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.
PreventionGenetics, part of Exact Sciences	RCV004755700	SCV005350713	pathogenic	TSEN54-related disorder	2024-03-24	no assertion criteria provided	clinical testing	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.