rs386833655
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000310.4(PPT1):c.550G>A(p.Glu184Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,574 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E184V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000310.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PPT1 | NM_000310.4 | c.550G>A | p.Glu184Lys | missense_variant | 6/9 | ENST00000642050.2 | NP_000301.1 | |
PPT1 | NM_001363695.2 | c.550G>A | p.Glu184Lys | missense_variant | 6/8 | NP_001350624.1 | ||
PPT1 | NM_001142604.2 | c.241G>A | p.Glu81Lys | missense_variant | 3/6 | NP_001136076.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PPT1 | ENST00000642050.2 | c.550G>A | p.Glu184Lys | missense_variant | 6/9 | NM_000310.4 | ENSP00000493153.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151930Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251404Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135870
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461644Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727130
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151930Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74190
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 1 Pathogenic:4
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 03, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 29, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 184 of the PPT1 protein (p.Glu184Lys). This variant is present in population databases (rs386833655, gnomAD 0.01%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077, 10679943, 17044973). 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: 56204). 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2023 | Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 11440996); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24997880, 17044973, 9793631, 10679943, 34380004, 21990111, 9664077, 10781062, 11440996) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2016 | The p.E184K pathogenic mutation (also known as c.550G>A), located in coding exon 6 of the PPT1 gene, results from a G to A substitution at nucleotide position 550. The glutamic acid at codon 184 is replaced by lysine, an amino acid with similar properties. This pathogenic mutation has been reported with a known pathogenic mutation and in the homozygous state in individuals with infantile neuronal ceroid lipofuscinoses (NCL) (Das AK et al. J Clin Invest. 1998; 102(2):361-70; Salonen T et al. Hum Mutat. 2000; 15(3):273-9). Functional studies in patient cells and in vitro studies found cells with this mutation had no detectable enzyme activity (Das AK et al. Hum Mol Genet. 2001; 10(13):1431-9). In addition, based on structural analysis, this mutation is expected to cause a conformational change in the palmitate-binding (Bellizzi JJ et al. Proc Natl Acad Sci USA. 2000; 97(9):4573-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 13, 2023 | Variant summary: PPT1 c.550G>A (p.Glu184Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251404 control chromosomes (gnomAD). c.550G>A has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (examples: Das_1998, Salonen_2000, and Bi_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Das_2001). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at