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

dbSNP: rs386833662

Total submissions: 7

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
Baylor Genetics	RCV000049622	SCV005052443	likely pathogenic	Neuronal ceroid lipofuscinosis 1	2024-02-14	criteria provided, single submitter	clinical testing
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.