rs386833639
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000310.4(PPT1):c.272A>C(p.Gln91Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q91E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000310.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PPT1 | NM_000310.4 | c.272A>C | p.Gln91Pro | missense_variant | 3/9 | ENST00000642050.2 | |
PPT1 | NM_001363695.2 | c.272A>C | p.Gln91Pro | missense_variant | 3/8 | ||
PPT1 | NM_001142604.2 | c.125-2623A>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PPT1 | ENST00000642050.2 | c.272A>C | p.Gln91Pro | missense_variant | 3/9 | NM_000310.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251460Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135896
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461794Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727214
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 1 Pathogenic:2Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 17, 2020 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 91 of the PPT1 protein (p.Gln91Pro). This variant is present in population databases (rs386833639, gnomAD 0.02%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 17044973; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56187). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 25, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at