VCV000520752.7 - ClinVar

NM_024312.5(GNPTAB):c.1959_1960del (p.Pro655fs)

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.

(5)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024312.5(GNPTAB):c.1959_1960del (p.Pro655fs)

Variation ID: 520752 Accession: VCV000520752.7

Type and length

Deletion, 2 bp

Location

Cytogenetic: 12q23.2 12: 101764957-101764958 (GRCh38) [ NCBI UCSC ] 12: 102158735-102158736 (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	Apr 15, 2018	Nov 3, 2024	Jan 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024312.5:c.1959_1960del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_077288.2:p.Pro655fs	frameshift
NM_024312.4:c.1959_1960del
NM_024312.4:c.1959_1960delTA
NC_000012.12:g.101764957_101764958del
NC_000012.11:g.102158735_102158736del
NG_021243.1:g.70910_70911del

... more HGVS ... less HGVS

Protein change

P655fs

Other names

Canonical SPDI

NC_000012.12:101764956:TA:

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

Links

ClinGen: CA607597818 dbSNP: rs1429181351 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.
GNPTAB		-	-	GRCh38 GRCh37	1561	1582

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.
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Aug 31, 2015	RCV000623566.2
Pseudo-Hurler polydystrophy	Likely pathogenic (1)	criteria provided, single submitter	May 25, 2018	RCV000853306.1
Mucolipidosis type II	Pathogenic (1)	criteria provided, single submitter	Feb 27, 2019	RCV001329953.1
Mucolipidosis type II Pseudo-Hurler polydystrophy	Pathogenic (1)	criteria provided, single submitter	Dec 5, 2023	RCV003767822.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jan 3, 2024	RCV004773044.1

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.
Likely pathogenic (May 25, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MUCOLIPIDOSIS III ALPHA/BETA Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996150.1 First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019	Comment: This frameshifting variant in exon 13 of 21 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. … (more) This frameshifting variant in exon 13 of 21 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has not been previously reported or functionally characterized in the literature to our knowledge. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/246184) and thus is presumed to be rare. Based on the available evidence, the c.1959_1960delTA (p.Pro655HisfsTer12) variant is classified as likely pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (Feb 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucolipidosis type II Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001521522.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Aug 31, 2015)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741015.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Number of individuals with the variant: 1 Clinical Features: Multiple prenatal fractures (present) , Osteopenia (present) , Growth delay (present) , Hearing impairment (present) , Pulmonic stenosis (disease) (present) , Anteriorly placed anus (present) … (more) Multiple prenatal fractures (present) , Osteopenia (present) , Growth delay (present) , Hearing impairment (present) , Pulmonic stenosis (disease) (present) , Anteriorly placed anus (present) , Bowing of the legs (present) , Muscular hypotonia of the trunk (present) , Hand clenching (present) , Oligohydramnios (present) , Intrauterine growth retardation (present) , Atrial septal defect (present) , Patent ductus arteriosus after birth at term (present) , Periorbital fullness (present) , Hypertelorism (present) , Retrognathia (present) , Relative macrocephaly (present) , Brachycephaly (present) , Slanting of the palpebral fissure (present) , Smooth philtrum (present) , Thin vermilion border (present) , Low-set ears (present) , Heterochromia iridis (present) , Abnormality of the skeletal system (present) (less) Sex: male Ethnicity/Population group: Hispanic
Pathogenic (Dec 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Pseudo-Hurler polydystrophy Mucolipidosis type II Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004568068.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 19617216‚ 25107912‚ 34645491 Comment: This sequence change creates a premature translational stop signal (p.Pro655Hisfs12) in the GNPTAB gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Pro655Hisfs12) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of mucolipdosis III alpha/beta (PMID: 34645491). ClinVar contains an entry for this variant (Variation ID: 520752). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jan 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: SCV005384188.1 First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Classified as a likely pathogenic variant; however additional supporting evidence was not described (PMID: 34645491); This variant is associated with the following publications: (PMID: 34645491) (less)

Comment:

This frameshifting variant in exon 13 of 21 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has not been previously reported or functionally characterized in the literature to our knowledge. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/246184) and thus is presumed to be rare. Based on the available evidence, the c.1959_1960delTA (p.Pro655HisfsTer12) variant is classified as likely pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Pro655Hisfs*12) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of mucolipdosis III alpha/beta (PMID: 34645491). ClinVar contains an entry for this variant (Variation ID: 520752). For these reasons, this variant has been classified as Pathogenic.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Classified as a likely pathogenic variant; however additional supporting evidence was not described (PMID: 34645491); This variant is associated with the following publications: (PMID: 34645491)

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
Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases.	De La Vega FM	Genome medicine	2021	PMID: 34645491
A novel mouse model of a patient mucolipidosis II mutation recapitulates disease pathology.	Paton L	The Journal of biological chemistry	2014	PMID: 25107912
Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands.	Cathey SS	Journal of medical genetics	2010	PMID: 19617216

Text-mined citations for rs1429181351 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_024312.5(GNPTAB):c.1959_1960del (p.Pro655fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1429181351 ...