ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1094G>A (p.Cys365Tyr)

gnomAD frequency: 0.00005  dbSNP: rs119455954
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000002761 SCV000220456 likely pathogenic Neuronal ceroid lipofuscinosis 2 2014-06-26 criteria provided, single submitter literature only
GeneDx RCV000189781 SCV000243429 pathogenic not provided 2022-03-10 criteria provided, single submitter clinical testing Published functional studies have shown a decrease in TPP1 protease activity in the fibroblasts of affected patients (Sleat et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25326635, 19038966, 19038967, 10330339, 21990111, 19246452, 9788728, 29655203, 32146219, 32329550, 31283065, 31589614, 33268510, 26822727, 23042927, 26075876, 30771299, 9295267)
Invitae RCV000189781 SCV000628893 pathogenic not provided 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 365 of the TPP1 protein (p.Cys365Tyr). This variant is present in population databases (rs119455954, gnomAD 0.004%). This missense change has been observed in individual(s) with late infantile neuronal ceroid lipofuscinosis (PMID: 9788728, 10330339, 26075876). This variant is also known as c.4655G>A and c.1107T>C. ClinVar contains an entry for this variant (Variation ID: 2642). 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 expected to disrupt TPP1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000526403 SCV000696662 pathogenic Neuronal ceroid lipofuscinosis 2016-12-30 criteria provided, single submitter clinical testing Variant summary: The TPP1 c.1094G>A (p.Cys365Tyr) variant located in the Peptidase S8/S53 domain (via InterPro) causes a missense change involving the alteration of a Cysteine, which has been implicated to play a key role in disulfide linkages needed to stabilize the fold (Guhaniyogi_2009 (PMID: 19038967). In addition, 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121330 (1/60665), which does not exceed the estimated maximal expected allele frequency for a pathogenic TPP1 variant of 1/338. Multiple publications cite individuals affected with Late-Infantile Neuronal Ceroid-Lipofuscinoses, who are homozygous or compound heterozygous for the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic" or "pathogenic." Therefore, the variant of interest has been classified as "Pathogenic."
Baylor Genetics RCV000002761 SCV000807625 pathogenic Neuronal ceroid lipofuscinosis 2 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found twice in our laboratory in trans with another pathogenic variant: with W366X in a 7-year-old male with developmental delay/regression, hypertonia/spasticity, seizure, ataxia, myoclonus, progressive brain atrophy, vision loss; with c.509-1G>C in a 5-year-old male with developmental regression, truncal ataxia, seizure disorder, optic atrophy, diffuse brain atrophy. Heterozygotes are expected to be asymptomatic carriers.
CeGaT Center for Human Genetics Tuebingen RCV000189781 SCV001249320 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000189781 SCV002022409 pathogenic not provided 2022-11-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002496238 SCV002807609 pathogenic Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7 2022-05-27 criteria provided, single submitter clinical testing
OMIM RCV000002761 SCV000022919 pathogenic Neuronal ceroid lipofuscinosis 2 1997-09-19 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000002761 SCV000091183 not provided Neuronal ceroid lipofuscinosis 2 no assertion provided not provided

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