rs137852695

chr1-40091398-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

The NM_000310.4(PPT1):c.364A>T(p.Arg122Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,613,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: PPT1 NM_000310.4 missense, splice_region
• Scores: Splicing: ADA: 0.02228
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 1.89

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 11 ACMG points.

• PM1: In a helix (size 11) in uniprot entity PPT1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000310.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-40091398-T-A is Pathogenic according to our data. Variant chr1-40091398-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 8899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40091398-T-A is described in Lovd as [Pathogenic]. Variant chr1-40091398-T-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.016265899).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPT1	NM_000310.4	c.364A>T	p.Arg122Trp	missense_variant, splice_region_variant	4/9	ENST00000642050.2
PPT1	NM_001363695.2	c.364A>T	p.Arg122Trp	missense_variant, splice_region_variant	4/8
PPT1	NM_001142604.2	c.125-1886A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPT1	ENST00000642050.2	c.364A>T	p.Arg122Trp	missense_variant, splice_region_variant	4/9		NM_000310.4	P1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152110 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.00755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000703 AC: 176 AN: 250432 Hom.: 0 AF XY: 0.000724 AC XY: 98 AN XY: 135374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00648

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000298 AC: 436 AN: 1460870 Hom.: 0 Cov.: 32 AF XY: 0.000297 AC XY: 216 AN XY: 726742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00678

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152228 Hom.: 0 Cov.: 31 AF XY: 0.000927 AC XY: 69 AN XY: 74414

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00755

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000642 AC: 78

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:10 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2019	Variant summary: PPT1 c.364A>T (p.Arg122Trp) 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 0.0007 in 250432 control chromosomes (gnomAD). c.364A>T has been reported in the literature in numerous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and is considered a Finnish founder mutation. The variant has been functionally shown to impact enzyme activity (Vesa_1995). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000310.3(PPT1):c.364A>T(R122W) is classified as pathogenic in the context of PPT1-related neuronal ceroid lipofuscinosis and is associated with the infantile form of this disease. Sources cited for classification include the following: PMID 7637805. Classification of NM_000310.3(PPT1):c.364A>T(R122W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 122 of the PPT1 protein (p.Arg122Trp). This variant is present in population databases (rs137852695, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with infantile neuronal ceroid lipofuscinosis (INCL) (PMID: 7637805, 9664077, 26795593). It is commonly reported in individuals of Finnish ancestry (PMID: 7637805, 9664077, 19941651, 21990111, 26795593; INCL). ClinVar contains an entry for this variant (Variation ID: 8899). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PPT1 function (PMID: 7637805, 10781062). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Apr 12, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000310.3:c.364A>T in the PPT1 gene has an allele frequency of 0.006 in European(Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that c.364A>T has impaired enzyme activity(PMID: 7637805). Helbig et al. reported a child with progressive Myoclonus Epilepsy barboring the compound heterozygous of c.364A>T (p.R122W) and c.353G>A (p.G118D) (PMID: 26795593); In addition, Vesa et al. reported that 40 of the 42 Finnish families, whose child were homozygous suffering Ceroid lipofuscinosis neuronal, and parents were heterozygous, suggesting a founder effect in Finnish population (PMID: 7637805); Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS4; PS3; PM3; PP4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 17, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 17, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 13, 2019	PS3, PS4, PM3, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2022	Published functional studies demonstrate a damaging effect resulting in impairment of enzyme activity (Lyly et al., 2007; Vesa et al., 1995); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20561933, 22778232, 14997939, 11754099, 26026925, 16759889, 24997880, 16542649, 12069847, 19793631, 26795593, 9664077, 17388982, 10781062, 20346914, 16644870, 19941651, 16930952, 11073228, 25091425, 25865307, 7637805, 25525159, 21228398, 21990111, 28559085, 31980526, 17565660, 33726816) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2016

The p.R122W pathogenic mutation (also known as c.364A>T), located in coding exon 4 of the PPT1 gene, results from an A to T substitution at nucleotide position 364. The arginine at codon 122 is replaced by tryptophan, an amino acid with dissimilar properties. This pathogenic mutation has been identified in the homozygous state or with another alteration in PPT1 in multiple individuals with infantile neuronal ceroid lipofuscinoses (NCL) and is a founder mutation in the Finnish population (Vesa J et al. Nature. 1995; 376(6541):584-7; Das AK et al. J Clin Invest. 1998; 102(2):361-70; Kousi M et al. Hum Mutat. 2012; 33(1):42-63). Functional studies in patient cells and in vitro studies have found this mutation to result in undetectable enzyme activity and accumulation of the polypeptide in the endoplasmic reticulum (Vesa J et al. Nature. 1995; 376(6541):584-7; Das AK et al. Hum Mol Genet. 2001;10(13):1431-9; Lyly A et al. BMC Cell Biol. 2007; 8:22). In addition, based on structural analysis, this mutation is anticipated to result in a significant decrease in structural stability (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, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Jul 06, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.19	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.016	T
MutationTaster	Benign	1.0	A;A
ClinPred		0.46	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.022
dbscSNV1_RF	Benign	0.28
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: rs137852695; hg19: chr1-40557070;