Submissions for variant NM_025265.4(TSEN2):c.926A>G (p.Tyr309Cys)

gnomAD frequency: 0.00001  dbSNP: rs113994149

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000002207	SCV000746778	pathogenic	Pontocerebellar hypoplasia type 2B	2017-12-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000002207	SCV001520857	likely pathogenic	Pontocerebellar hypoplasia type 2B		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824558	SCV002074164	likely pathogenic	Pontoneocerebellar hypoplasia	2022-01-09	criteria provided, single submitter	clinical testing	Variant summary: TSEN2 c.926A>G (p.Tyr309Cys) results in a non-conservative amino acid change located in the tRNA intron endonuclease, N-terminal domain (IPR006678) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Multiple sequence alignment of human TSEN2 with the corresponding sequences of a broad range of other organisms showed that the Tyr309 position is strictly conserved (tyrosine or phenylalanine) within eukaryotic organisms (Budde_2008). The variant allele was found at a frequency of 0.00014 in 251398 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in TSEN2 causing Pontocerebellar Hypoplasia, Type 2B (0.00014 vs 0.0011), allowing no conclusion about variant significance. Moreover, the single homozygote observed in gnomAD database has been reported as not a true homozygote due to one read supporting a reference base (Tarailo-Graovac_2017). c.926A>G has been reported in the literature as a homozygous and compound heterozygous genotype in individuals affected with Pontocerebellar Hypoplasia, Type 2B (example, Budde_2008, Namavar_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV002512672	SCV003525023	uncertain significance	not provided	2022-08-09	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 2125). This missense change has been observed in individual(s) with pontocerebellar hypoplasias (PMID: 18711368, 20952379). This variant is present in population databases (rs113994149, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 309 of the TSEN2 protein (p.Tyr309Cys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").
OMIM	RCV000002207	SCV000022365	pathogenic	Pontocerebellar hypoplasia type 2B	2011-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000002207	SCV000041516	not provided	Pontocerebellar hypoplasia type 2B		no assertion provided	literature only