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NM_000310.4(PPT1):c.234+2T>G AND Neuronal ceroid lipofuscinosis 1

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Aug 2, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002488682.1

Allele description [Variation Report for NM_000310.4(PPT1):c.234+2T>G]

NM_000310.4(PPT1):c.234+2T>G

Gene:
PPT1:palmitoyl-protein thioesterase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p34.2
Genomic location:
Preferred name:
NM_000310.4(PPT1):c.234+2T>G
HGVS:
  • NC_000001.11:g.40092396A>C
  • NG_009192.1:g.10075T>G
  • NM_000310.4:c.234+2T>GMANE SELECT
  • NM_001142604.2:c.125-2884T>G
  • NM_001363695.2:c.234+2T>G
  • LRG_690:g.10075T>G
  • NC_000001.10:g.40558068A>C
Molecular consequence:
  • NM_001142604.2:c.125-2884T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000310.4:c.234+2T>G - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001363695.2:c.234+2T>G - splice donor variant - [Sequence Ontology: SO:0001575]
Functional consequence:
loss_of_function_variant [Sequence Ontology: SO:0002054]
Observations:
1

Condition(s)

Name:
Neuronal ceroid lipofuscinosis 1 (CLN1)
Synonyms:
CEROID LIPOFUSCINOSIS, NEURONAL, 1, VARIABLE AGE AT ONSET; CLN1 variable age at onset; Infantile CLN (type of CLN1); See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009744; MedGen: C1850451; OMIM: 256730

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002769832Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Aug 2, 2022) 		unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
South Indian Hinduunknownyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences, SCV002769832.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1South Indian Hindu1not providednot providedclinical testing PubMed (1)

Description

The splice donor variant NM_000310.4(PPT1):c.234+2T>G has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.234+2T>G variant is novel (not in any individuals) in 1kG All. The c.234+2T>G variant is novel (not in any individuals) in gnomAD. This variant mutates a splice-donor sequence, potentially resulting in the retention of large segments of intronic DNA by the mRNA and nonfunctional proteins. This variant results in the loss of an donor splice site for the clinically relevant transcript. This variant disrupts the donor splice site for an exon upstream from the penultimate exon junction and is therefore predicted to cause nonsense mediated decay. The c.234+2T>G variant is a loss of function variant in the gene PPT1, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_000301.1:p.M1K and 19 others. For these reasons, this variant has been classified as Likely Pathogenic.

Description

The c.234+2T>G variant has been observed in homozygous state in the individual with clinically suspected Neuronal Ceroid Lipofuscinosis (the individual had infantile onset of seizures, regression of milestones along with imaging findings of hypointense thalami and confluent periventricular white matter hyperintensity) which is an autosomal recessive disorder. The variant is novel (not observed in any individuals in 1KG, gnomAD and our inhouse database).This variant mutates a splice-donor sequence, potentially resulting in the retention of large segments of intronic DNA by the mRNA and nonfunctional proteins. This variant results in the loss of an donor splice site for the clinically relevant transcript. This variant disrupts the donor splice site for an exon upstream from the penultimate exon junction and is therefore predicted to cause nonsense mediated decay. The c.234+2T>G variant is a loss of function variant in the gene PPT1, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_000301.1:p.M1K and 19 others. For these reasons, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Jun 10, 2023