ClinVar Miner

Submissions for variant NM_000310.4(PPT1):c.325T>G (p.Tyr109Asp)

gnomAD frequency: 0.00001  dbSNP: rs386833642
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188711 SCV000242335 pathogenic not provided 2022-02-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with significantly impaired enzyme activity (Das et al., 2001); 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: 17565660, 10191107, 21990111, 11440996, 9664077, 11073228, 15719035)
Invitae RCV000049601 SCV001219531 pathogenic Neuronal ceroid lipofuscinosis 1 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 109 of the PPT1 protein (p.Tyr109Asp). This variant is present in population databases (rs386833642, gnomAD 0.0009%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077, 10191107, 21990111). ClinVar contains an entry for this variant (Variation ID: 56190). 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 PPT1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PPT1 function (PMID: 11440996). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000049601 SCV002768749 pathogenic Neuronal ceroid lipofuscinosis 1 2020-05-25 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to aspartic acid (exon 3). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 Heterozygote, 0 Homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (palmitoyl protein thioesterase domain, PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Das, AK. et al. (1998), Hofmann, SL. et al. (1999), Das, AK. et al. (2001), Kousi, M. et al. (2012), Teixeira, C. et al. (2013)). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1001 - Strong functional evidence supporting abnormal protein function (Das, AK. et al. (2001)). (P) 1208 - Inheritance information for this variant is not currently available. (N)
Baylor Genetics RCV000049601 SCV004204140 pathogenic Neuronal ceroid lipofuscinosis 1 2023-09-02 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049601 SCV000082008 probable-pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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