VCV001916165.5 - ClinVar

NM_000478.6(ALPL):c.814del (p.Arg272fs)

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.

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_000478.6(ALPL):c.814del (p.Arg272fs)

Variation ID: 1916165 Accession: VCV001916165.5

Type and length

Deletion, 1 bp

Location

Cytogenetic: 1p36.12 1: 21570325 (GRCh38) [ NCBI UCSC ] 1: 21896818 (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 7, 2023	Jun 17, 2024	Nov 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000478.6:c.814del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000469.3:p.Arg272fs	frameshift
NM_001127501.4:c.649del	NP_001120973.2:p.Arg217fs	frameshift
NM_001177520.3:c.583del	NP_001170991.1:p.Arg195fs	frameshift
NM_001369803.2:c.814del	NP_001356732.1:p.Arg272fs	frameshift
NM_001369804.2:c.814del	NP_001356733.1:p.Arg272fs	frameshift
NM_001369805.2:c.814del	NP_001356734.1:p.Arg272fs	frameshift
NC_000001.11:g.21570326del
NC_000001.10:g.21896819del
NG_008940.1:g.65962del
NG_008940.2:g.66344del

... more HGVS ... less HGVS

Protein change

R195fs, R217fs, R272fs

Other names

Canonical SPDI

NC_000001.11:21570324:CC: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.

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	1213	1229

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	Pathogenic (1)	criteria provided, single submitter	Oct 12, 2023	RCV002594376.3
Adult hypophosphatasia	Likely pathogenic (1)	criteria provided, single submitter	Nov 30, 2023	RCV003465790.2

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.
Pathogenic (Oct 12, 2023)	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: SCV002957832.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 3174660‚ 10679946‚ 32973344‚ 33814268‚ 29236161 Comment: This sequence change creates a premature translational stop signal (p.Arg272Alafs5) in the ALPL gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg272Alafs5) in the ALPL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALPL are known to be pathogenic (PMID: 3174660, 10679946, 32973344, 33814268). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 29236161). ClinVar contains an entry for this variant (Variation ID: 1916165). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Nov 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adult hypophosphatasia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004193272.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

This sequence change creates a premature translational stop signal (p.Arg272Alafs*5) in the ALPL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALPL are known to be pathogenic (PMID: 3174660, 10679946, 32973344, 33814268). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 29236161). ClinVar contains an entry for this variant (Variation ID: 1916165). For these reasons, this variant has been classified as Pathogenic.

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
Investigation of ALPL variant states and clinical outcomes: An analysis of adults and adolescents with hypophosphatasia treated with asfotase alfa.	Kishnani PS	Molecular genetics and metabolism	2021	PMID: 33814268
Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation.	Mornet E	European journal of human genetics : EJHG	2021	PMID: 32973344
Genetic analysis of adults heterozygous for ALPL mutations.	Taillandier A	Journal of bone and mineral metabolism	2018	PMID: 29236161
Fifteen new mutations (-195C>T, L-12X, 298-2A>G, T117N, A159T, R229S, 997+2T>A, E274X, A331T, H364R, D389G, 1256delC, R433H, N461I, C472S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with hypophosphatasia.	Taillandier A	Human mutation	2000	PMID: 10679946
A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia.	Weiss MJ	Proceedings of the National Academy of Sciences of the United States of America	1988	PMID: 3174660

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000478.6(ALPL):c.814del (p.Arg272fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...