VCV000632629.12 - ClinVar

NM_000478.6(ALPL):c.1182dup (p.Ile395fs)

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_000478.6(ALPL):c.1182dup (p.Ile395fs)

Variation ID: 632629 Accession: VCV000632629.12

Type and length

Duplication, 1 bp

Location

Cytogenetic: 1p36.12 1: 21575916-21575917 (GRCh38) [ NCBI UCSC ] 1: 21902409-21902410 (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	Jun 2, 2019	Feb 20, 2024	Dec 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000478.6:c.1182dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000469.3:p.Ile395fs	frameshift
NM_000478.6:c.1182dupT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001127501.4:c.1017dup	NP_001120973.2:p.Ile340fs	frameshift
NM_001177520.3:c.951dup	NP_001170991.1:p.Ile318fs	frameshift
NM_001369803.2:c.1182dup	NP_001356732.1:p.Ile395fs	frameshift
NM_001369804.2:c.1182dup	NP_001356733.1:p.Ile395fs	frameshift
NM_001369805.2:c.1182dup	NP_001356734.1:p.Ile395fs	frameshift
NC_000001.11:g.21575917dup
NC_000001.10:g.21902410dup
NG_008940.1:g.71553dup

... more HGVS ... less HGVS

Protein change

I318fs, I395fs, I340fs

Other names

Canonical SPDI

NC_000001.11:21575916:T:TT

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

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs754826836 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	1210	1226

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	Likely pathogenic (1)	criteria provided, single submitter	Aug 20, 2018	RCV000779692.1
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 14, 2023	RCV001055790.6
Adult hypophosphatasia	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 25, 2023	RCV001198564.3
Childhood hypophosphatasia	Pathogenic (1)	criteria provided, single submitter	Dec 2, 2020	RCV001281691.1

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 (Aug 20, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hypophosphatasia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000916443.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Comment: Variant summary: ALPL c.1182dupT (p.Ile395TyrfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: ALPL c.1182dupT (p.Ile395TyrfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 246234 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1182dupT in individuals affected with Hypophosphatasia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Likely pathogenic (Sep 05, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adult hypophosphatasia Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369553.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Pathogenic (Dec 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Childhood hypophosphatasia Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001469054.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021
Pathogenic (Dec 14, 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: SCV001220199.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 3174660‚ 10679946‚ 32973344‚ 33814268 Comment: This sequence change creates a premature translational stop signal (p.Ile395Tyrfs10) 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.Ile395Tyrfs10) 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 present in population databases (rs754826836, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ALPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 632629). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jul 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adult hypophosphatasia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004194941.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023

Comment:

Variant summary: ALPL c.1182dupT (p.Ile395TyrfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 246234 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1182dupT in individuals affected with Hypophosphatasia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ile395Tyrfs*10) 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 present in population databases (rs754826836, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ALPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 632629). 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
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 rs754826836 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000478.6(ALPL):c.1182dup (p.Ile395fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs754826836 ...