VCV002095404.5 - ClinVar

NM_002778.4(PSAP):c.722_723delinsAA (p.Cys241Ter)

Germline

Classification

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

Pathogenic/Likely pathogenic

2 out of 2 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_002778.4(PSAP):c.722_723delinsAA (p.Cys241Ter)

Variation ID: 2095404 Accession: VCV002095404.5

Type and length

Indel, 2 bp

Location

Cytogenetic: 10q22.1 10: 71825891-71825892 (GRCh38) [ NCBI UCSC ] 10: 73585648-73585649 (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	Feb 8, 2023	Apr 4, 2026	Nov 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002778.4:c.722_723delinsAA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002769.1:p.Cys241Ter	nonsense
NM_001042465.3:c.722_723delinsAA	NP_001035930.1:p.Cys241Ter	nonsense
NM_001042466.3:c.722_723delinsAA	NP_001035931.1:p.Cys241Ter	nonsense
NM_002778.3:c.722_723delinsAA
NC_000010.11:g.71825891_71825892delinsTT
NC_000010.10:g.73585648_73585649delinsTT
NG_009301.1:g.30434_30435delinsAA

... more HGVS ... less HGVS

Protein change

C241*

Other names

Canonical SPDI

NC_000010.11:71825890:GC:TT

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.

Links

ClinGen: CA2580081931 dbSNP: rs2494516881 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.
PSAP		-	-	GRCh38 GRCh37	1000	1026

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.
Sphingolipid activator protein 1 deficiency	Pathogenic (1)	criteria provided, single submitter	Mar 10, 2022	RCV003013783.5
Metachromatic leukodystrophy	Likely pathogenic (1)	criteria provided, single submitter	Nov 20, 2024	RCV006641117.1

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.	Expand all rows Collapse all rows 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 10, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Sphingolipid activator protein 1 deficiency	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003307281.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 23, 2026	Publications: PubMed (5) PubMed: 11309366‚ 17616409‚ 19267410‚ 30632081‚ 8554069 Comment: show For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PSAP-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Cys241*) in the PSAP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PSAP are known to be pathogenic (PMID: 8554069, 11309366, 17616409, 19267410, 30632081). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Nov 20, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Metachromatic leukodystrophy	Natera, Inc. Accession: SCV007527501.1 First in ClinVar: Apr 04, 2026 Last updated: Apr 04, 2026	Comment: show The c.722_723delinsAA variant in PSAP is a deletion-insertion (delins) variant predicted to replace one or more nucleotides with a different sequence. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). Given the available evidence, this variant is classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PSAP-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Cys241*) in the PSAP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PSAP are known to be pathogenic (PMID: 8554069, 11309366, 17616409, 19267410, 30632081).

Comment:

The c.722_723delinsAA variant in PSAP is a deletion-insertion (delins) variant predicted to replace one or more nucleotides with a different sequence. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). Given the available evidence, this variant is classified as Likely Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Late Infantile Metachromatic Leukodystrophy Due to Novel Pathogenic Variants in the PSAP Gene.	Kolnikova M	Journal of molecular neuroscience : MN	2019	PMID: 30632081
Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations.	Kuchar L	American journal of medical genetics. Part A	2009	PMID: 19267410
Metachromatic leukodystrophy without arylsulfatase A deficiency: a new case of saposin-B deficiency.	Deconinck N	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2008	PMID: 17616409
A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation.	Hulková H	Human molecular genetics	2001	PMID: 11309366
Analysis of a splice-site mutation in the sap-precursor gene of a patient with metachromatic leukodystrophy.	Henseler M	American journal of human genetics	1996	PMID: 8554069

Text-mined citations for rs2494516881 ...

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 Apr 04, 2026