Submissions for variant NM_207346.3(TSEN54):c.371G>T (p.Gly124Val)

gnomAD frequency: 0.00002  dbSNP: rs774157225

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000585886	SCV000693770	likely pathogenic	Pontocerebellar hypoplasia type 2A	2018-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV002469213	SCV002765757	likely pathogenic	not provided	2022-06-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 31589614, 30315573, 29302074, 20952379, 32404165)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117356	SCV003801320	pathogenic	Pontoneocerebellar hypoplasia	2023-01-04	criteria provided, single submitter	clinical testing	Variant summary: TSEN54 c.371G>T (p.Gly124Val) results in a non-conservative amino acid change located in the tRNA-splicing endonuclease, subunit Sen54, N-terminal domain (IPR024336) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251156 control chromosomes (gnomAD database). c.371G>T has been reported in the literature in individuals affected with Pontocerebellar Hypoplasia (PCH) (examples: Namavar_2011 and Pode-Shakked_2021) and intellectual disability with features of PCH (examples: Hu_2019 and Issa_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1), likely pathogenic (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002469213	SCV004297530	likely pathogenic	not provided	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 124 of the TSEN54 protein (p.Gly124Val). This variant is present in population databases (rs774157225, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of pontocerebellar hypoplasia (PMID: 20952379, 29302074, 30315573, 34580403). ClinVar contains an entry for this variant (Variation ID: 495240). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Pediatric Genetics Clinic, Sheba Medical Center	RCV000585886	SCV001712245	pathogenic	Pontocerebellar hypoplasia type 2A	2021-05-13	no assertion criteria provided	clinical testing