VCV000056213.12 - ClinVar

NM_000310.4(PPT1):c.727-2A>T

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

4 out of 5 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000310.4(PPT1):c.727-2A>T

Variation ID: 56213 Accession: VCV000056213.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.2 1: 40076915 (GRCh38) [ NCBI UCSC ] 1: 40542587 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 24, 2013	Jun 8, 2025	Oct 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000310.4:c.727-2A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001142604.2:c.418-2A>T		splice acceptor
NM_001363695.2:c.726+1645A>T		intron variant
NC_000001.11:g.40076915T>A
NC_000001.10:g.40542587T>A
NG_009192.1:g.25556A>T
LRG_690:g.25556A>T
LRG_690t1:c.727-2A>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:40076914:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA263545 dbSNP: rs386833664 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PPT1		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	719	749

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Neuronal ceroid lipofuscinosis 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 23, 2024	RCV000049624.10
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2017	RCV000224164.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 28, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281082.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Platform type: Sequencing Platform name: Illumina

Likely pathogenic (Jan 31, 2017) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568387.4 First in ClinVar: Jun 08, 2016 Last updated: May 03, 2018	Comment: A c.727-2 A>T variant that is likely pathogenic has been identified in the PPT1 gene. The c.727-2 A>T variant was previously reported in one patient … (more) A c.727-2 A>T variant that is likely pathogenic has been identified in the PPT1 gene. The c.727-2 A>T variant was previously reported in one patient with infantile neuronal ceroid lipofuscinoses, with known palmitoyl-protein thioesterase deficiency, who also harbored a second PPT1 pathogenic variant, however phase was not reported (Das et al., 1998). The c.727-2 A>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.727-2 A>T splice site variant gene destroys the canonical splice acceptor site in intron 7. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. (less)

Pathogenic (Oct 23, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001421942.6 First in ClinVar: Jul 16, 2020 Last updated: Feb 25, 2025	Publications: PubMed (4) PubMed: 16199547‚ 10679943‚ 21990111‚ 9664077 Comment: This sequence change affects an acceptor splice site in intron 7 of the PPT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects an acceptor splice site in intron 7 of the PPT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943, 21990111). This variant is present in population databases (rs386833664, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077). This variant is also known as T (IVS7, -2). ClinVar contains an entry for this variant (Variation ID: 56213). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)

Pathogenic (Mar 04, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005052440.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: not provided	Ceroid lipofuscinosis neuronal 1 Affected status: not provided Allele origin: unknown	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) Accession: SCV000082031.2 First in ClinVar: Jul 24, 2013 Last updated: Jun 08, 2025 Comment: FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference	Comment: Converted during submission from probable-pathogenic to Likely pathogenic.

Comment:

A c.727-2 A>T variant that is likely pathogenic has been identified in the PPT1 gene. The c.727-2 A>T variant was previously reported in one patient with infantile neuronal ceroid lipofuscinoses, with known palmitoyl-protein thioesterase deficiency, who also harbored a second PPT1 pathogenic variant, however phase was not reported (Das et al., 1998). The c.727-2 A>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.727-2 A>T splice site variant gene destroys the canonical splice acceptor site in intron 7. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

Comment:

This sequence change affects an acceptor splice site in intron 7 of the PPT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943, 21990111). This variant is present in population databases (rs386833664, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077). This variant is also known as T (IVS7, -2). ClinVar contains an entry for this variant (Variation ID: 56213). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses.	Kousi M	Human mutation	2012	PMID: 21990111
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Detection of eight novel palmitoyl protein thioesterase (PPT) mutations underlying infantile neuronal ceroid lipofuscinosis (INCL;CLN1).	Salonen T	Human mutation	2000	PMID: 10679943
Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S.	Das AK	The Journal of clinical investigation	1998	PMID: 9664077

Text-mined citations for rs386833664 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 08, 2025

ClinVar Genomic variation as it relates to human health

NM_000310.4(PPT1):c.727-2A>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs386833664 ...