rs386833645

Positions:

• chr1-40097236-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000310.4(PPT1):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000031 in 1,613,764 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PPT1 NM_000310.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.74

Genes affected

PPT1 (HGNC:9325): (palmitoyl-protein thioesterase 1) The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000310.4 (PPT1) was described as [Likely_pathogenic] in ClinVar as 206651
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-40097236-C-T is Pathogenic according to our data. Variant chr1-40097236-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40097236-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPT1	NM_000310.4	c.3G>A	p.Met1?	start_lost	1/9	ENST00000642050.2
PPT1	NM_001363695.2	c.3G>A	p.Met1?	start_lost	1/8
PPT1	NM_001142604.2	c.3G>A	p.Met1?	start_lost	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPT1	ENST00000642050.2	c.3G>A	p.Met1?	start_lost	1/9		NM_000310.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461536 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727106

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:4

Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
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	Nov 21, 2023	This sequence change affects the initiator methionine of the PPT1 mRNA. The next in-frame methionine is located at codon 41. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077, 11073228, 11440996). ClinVar contains an entry for this variant (Variation ID: 56193). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects PPT1 function (PMID: 11440996). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 08, 2014	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2021

The c.3G>A (p.M1?) alteration is located in coding exon 1 of the PPT1 gene and results from a G to A substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. This mutation was identified in two individuals with neuronal ceroid lipofuscinosis in conjunction with a second PPT1 variant (Das, 1998). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2022

Published functional studies demonstrate a damaging effect suggesting a partial defect in protein expression (Lyly et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10191107, 33561134, 9664077, 17565660, 11440996, 29631617, 11073228) -

Neuronal ceroid lipofuscinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 31, 2023

Variant summary: PPT1 c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 247912 control chromosomes (gnomAD, v2). c.3G>A has been reported in the literature in at least three individuals affected with late-infantile or juvenile-onset Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Das_1998, Hofmann_1999). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated a greatly reduced protein expression, with a largely preserved specific activity in transfected cells, which was in accordance with the significantly reduced enzyme activity in patient derived cell lines (Das_2001, Lyly_2007, Sima_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;.;.;.;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationTaster	Benign	1.0	D;D
Polyphen		0.81	P;.;.;.;.;P;.
Vest4		0.96, 0.96
MutPred		0.58		Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);
MVP		0.97
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.94
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386833645; hg19: chr1-40562908;