VCV002671820.2 - ClinVar

NM_000478.6(ALPL):c.297+5G>A

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.

(2)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000478.6(ALPL):c.297+5G>A

Variation ID: 2671820 Accession: VCV002671820.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.12 1: 21561217 (GRCh38) [ NCBI UCSC ] 1: 21887710 (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 17, 2023	Feb 20, 2024	Jun 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000478.6:c.297+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001127501.4:c.132+5G>A		intron variant
NM_001177520.3:c.66+472G>A		intron variant
NM_001369803.2:c.297+5G>A		intron variant
NM_001369804.2:c.297+5G>A		intron variant
NM_001369805.2:c.297+5G>A		intron variant
NC_000001.11:g.21561217G>A
NC_000001.10:g.21887710G>A
NG_008940.1:g.56853G>A
NG_008940.2:g.57235G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:21561216:G: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.

Links

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.
ALPL		-	-	GRCh38 GRCh37	1216	1232

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.
Hypophosphatasia	Uncertain significance (1)	criteria provided, single submitter	Jun 20, 2023	RCV003448902.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Nov 29, 2022	RCV003661056.2

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 (Jun 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypophosphatasia Affected status: yes Allele origin: germline	JKU Lab, Dept of Paediatrics, Johannes Kepler University Accession: SCV004175885.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (3) PubMed: 33827627‚ 36514157‚ 34924504 Comment: Absent in GnomAD. The ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/ Comment on evidence: A compound het case also reported c.[410delC];[297+5G>A]. Variant c.410del is not in ClinVar
Uncertain significance (Nov 29, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004376769.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 17576681‚ 9536098‚ 33827627 Comment: In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more) In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with hypophosphatasia (PMID: 33827627). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs776187726, gnomAD 0.004%). This sequence change falls in intron 4 of the ALPL gene. It does not directly change the encoded amino acid sequence of the ALPL protein. It affects a nucleotide within the consensus splice site. (less)

Comment:

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with hypophosphatasia (PMID: 33827627). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs776187726, gnomAD 0.004%). This sequence change falls in intron 4 of the ALPL gene. It does not directly change the encoded amino acid sequence of the ALPL protein. It affects a nucleotide within the consensus splice site.

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
Identifying adult hypophosphatasia in the rheumatology unit.	Feurstein J	Orphanet journal of rare diseases	2022	PMID: 36514157
Rathbun syndrome (hypophosphatasia) due to the heterozygous variant c.297+5G>A in alkaline phosphatase with unusual phenotype.	Finsterer J	Chinese medical journal	2021	PMID: 34924504
Clinical and genetic characteristics of hypophosphatasia in Chinese children.	Liu M	Orphanet journal of rare diseases	2021	PMID: 33827627
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000478.6(ALPL):c.297+5G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...