Submissions for variant NM_000391.4(TPP1):c.1397T>G (p.Val466Gly)

gnomAD frequency: 0.00001  dbSNP: rs398122959

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001529105	SCV000628900	pathogenic	not provided	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 466 of the TPP1 protein (p.Val466Gly). This variant is present in population databases (rs398122959, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive spinocerebellar ataxia (PMID: 23418007). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89086). 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) has been performed at Invitae 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 TPP1 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001529105	SCV004012282	likely pathogenic	not provided	2023-01-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23775425, 34733232, 31059981, 31283065, 23418007)
OMIM	RCV000074609	SCV000108698	pathogenic	Autosomal recessive spinocerebellar ataxia 7	2013-05-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529105	SCV001741990	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529105	SCV001954909	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529105	SCV001968318	pathogenic	not provided		no assertion criteria provided	clinical testing