ClinVar Miner

Submissions for variant NM_000310.4(PPT1):c.674T>C (p.Phe225Ser)

dbSNP: rs386833662
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001778693 SCV002014863 pathogenic Neuronal ceroid lipofuscinosis 2021-10-11 criteria provided, single submitter clinical testing Variant summary: PPT1 c.674T>C (p.Phe225Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251426 control chromosomes (gnomAD). c.674T>C has been reported in the literature in multiple individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Mole_2001, Jilani_2019, Sangeeth_2019, Nouri_2021). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000049622 SCV002229838 uncertain significance Neuronal ceroid lipofuscinosis 1 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 225 of the PPT1 protein (p.Phe225Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 11589012). ClinVar contains an entry for this variant (Variation ID: 56211). 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. 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.
3billion RCV000049622 SCV004013871 likely pathogenic Neuronal ceroid lipofuscinosis 1 criteria provided, single submitter clinical testing The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.95). The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with PPT1-related disorder (ClinVar ID: VCV000056211/PMID: 11589012). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 11589012, 21990111, 31741823). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx RCV003328554 SCV004035749 likely pathogenic not provided 2023-03-13 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: 11589007, 11589012, 12125808, 14997939, 31741823, 34695666, Sangeeth_2019_Poster)
CeGaT Center for Human Genetics Tuebingen RCV003328554 SCV004704131 likely pathogenic not provided 2024-02-01 criteria provided, single submitter clinical testing PPT1: PM3:Strong, PM1, PM2, PP3
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049622 SCV000082029 probable-pathogenic Neuronal ceroid lipofuscinosis 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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