VCV000199009.55 - ClinVar

NM_000310.4(PPT1):c.904A>G (p.Ile302Val)

Germline

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.

(17)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(7); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000310.4(PPT1):c.904A>G (p.Ile302Val)

Variation ID: 199009 Accession: VCV000199009.55

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.2 1: 40074078 (GRCh38) [ NCBI UCSC ] 1: 40539750 (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	Dec 6, 2016	Oct 20, 2024	Apr 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000310.4:c.904A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000301.1:p.Ile302Val	missense
NM_001142604.2:c.595A>G	NP_001136076.1:p.Ile199Val	missense
NM_001363695.2:c.832A>G	NP_001350624.1:p.Ile278Val	missense
NC_000001.11:g.40074078T>C
NC_000001.10:g.40539750T>C
NG_009192.1:g.28393A>G
LRG_690:g.28393A>G
LRG_690t1:c.904A>G	LRG_690p1:p.Ile302Val

... more HGVS ... less HGVS

Protein change

I302V, I278V, I199V

Other names

p.I302V:ATA>GTA

Canonical SPDI

NC_000001.11:40074077:T:C

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.

0.00040 (C)

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

1000 Genomes Project 0.00040

1000 Genomes Project 30x 0.00047

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062

Trans-Omics for Precision Medicine (TOPMed) 0.00084

The Genome Aggregation Database (gnomAD) 0.00091

The Genome Aggregation Database (gnomAD), exomes 0.00115

Exome Aggregation Consortium (ExAC) 0.00131

Links

ClinGen: CA247958 dbSNP: rs146902902 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		-	-	GRCh38 GRCh37	696	724

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.
not provided	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Apr 3, 2024	RCV000435004.41
Neuronal ceroid lipofuscinosis 1	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Jan 30, 2024	RCV000515384.34
Intellectual disability	Uncertain significance (1)	no assertion criteria provided	Jan 1, 2019	RCV001252358.10
not specified	Benign (1)	no assertion criteria provided	-	RCV001706153.8
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	Aug 31, 2018	RCV002317064.9
PPT1-related disorder	Likely benign (1)	no assertion criteria provided	Apr 25, 2022	RCV003955098.2

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.
Uncertain significance (May 23, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611426.1 First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017
Likely benign (Aug 31, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000851748.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain Significance (Jul 13, 2016)	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: SCV000510906.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Converted during submission to Uncertain significance.
Uncertain significance (Mar 10, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000232942.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PPT1 http://www.ucl.ac.uk/ncl/mutatio… http://www.ucl.ac.uk/ncl/mutation.shtml Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000357389.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Oct 28, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713813.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Number of individuals with the variant: 1
Uncertain significance (Nov 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004236475.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Likely benign (Jan 30, 2024)	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: SCV000640464.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532
Uncertain significance (Apr 03, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242330.14 First in ClinVar: Aug 07, 2015 Last updated: Sep 16, 2024	Comment: Reported previously in the heterozygous state in a male individual with hypsarrhythmia, infantile spasms, and developmental delay who also harbored a de novo pathogenic variant … (more) Reported previously in the heterozygous state in a male individual with hypsarrhythmia, infantile spasms, and developmental delay who also harbored a de novo pathogenic variant in KCNQ2 and a variant in PCDH19 (PMID: 27861786); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27861786) (less)
Likely benign (Feb 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002062792.20 First in ClinVar: Jan 29, 2022 Last updated: Oct 20, 2024	Comment: PPT1: BS2 Number of individuals with the variant: 2
Likely benign (-)	no assertion criteria provided Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734025.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Uncertain significance (Jan 01, 2019)	no assertion criteria provided Method: clinical testing	Intellectual disability Affected status: yes Allele origin: unknown	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV001428112.1 First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020	Publications: PubMed (1) PubMed: 25741868
Likely benign (Nov 11, 2019)	no assertion criteria provided Method: clinical testing	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460029.1 First in ClinVar: Jan 01, 2021 Last updated: Jan 01, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927033.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971345.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely benign (Apr 25, 2022)	no assertion criteria provided Method: clinical testing	PPT1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004785186.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
not provided (-)	no classification provided Method: phenotyping only	Neuronal ceroid lipofuscinosis 1 Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000986819.1 First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019	Comment: Variant interpretted as Uncertain significance and reported on 05/31/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report … (more) Variant interpretted as Uncertain significance and reported on 05/31/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: EEG abnormality (present) , Seizures (present) Age: 0-9 years Sex: male Testing laboratory: GeneDx Date variant was reported to submitter: 2018-05-31 Testing laboratory interpretation: Uncertain significance
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Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

Reported previously in the heterozygous state in a male individual with hypsarrhythmia, infantile spasms, and developmental delay who also harbored a de novo pathogenic variant in KCNQ2 and a variant in PCDH19 (PMID: 27861786); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27861786)

Comment:

Variant interpretted as Uncertain significance and reported on 05/31/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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
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	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PPT1	-	-	-	-
http://www.ucl.ac.uk/ncl/mutation.shtml	-	-	-	-

Text-mined citations for rs146902902 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000310.4(PPT1):c.904A>G (p.Ile302Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs146902902 ...