VCV000288247.37 - ClinVar

NM_000478.6(ALPL):c.818C>T (p.Thr273Met)

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.

(11)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(4); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000478.6(ALPL):c.818C>T (p.Thr273Met)

Variation ID: 288247 Accession: VCV000288247.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.12 1: 21570330 (GRCh38) [ NCBI UCSC ] 1: 21896823 (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 6, 2016	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000478.6:c.818C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000469.3:p.Thr273Met	missense
NM_001127501.4:c.653C>T	NP_001120973.2:p.Thr218Met	missense
NM_001177520.3:c.587C>T	NP_001170991.1:p.Thr196Met	missense
NM_001369803.2:c.818C>T	NP_001356732.1:p.Thr273Met	missense
NM_001369804.2:c.818C>T	NP_001356733.1:p.Thr273Met	missense
NM_001369805.2:c.818C>T	NP_001356734.1:p.Thr273Met	missense
NC_000001.11:g.21570330C>T
NC_000001.10:g.21896823C>T
NG_008940.1:g.65966C>T

... more HGVS ... less HGVS

Protein change

T273M, T196M, T218M

Other names

Canonical SPDI

NC_000001.11:21570329:C:T

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) 0.00106

Trans-Omics for Precision Medicine (TOPMed) 0.00114

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00115

Exome Aggregation Consortium (ExAC) 0.00117

Links

ClinGen: CA666627 dbSNP: rs148405563 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.
Hypophosphatasia	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Oct 19, 2022	RCV000263557.9
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Jul 1, 2024	RCV000710516.31
Inborn genetic diseases	Benign (1)	criteria provided, single submitter	Jan 11, 2022	RCV002519300.2
not specified	Likely benign (1)	criteria provided, single submitter	Nov 22, 2021	RCV001820834.4
ALPL-related disorder	Likely benign (1)	no assertion criteria provided	Feb 2, 2024	RCV004549605.2

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.
Benign (Sep 30, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000840754.1 First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018	Publications: PubMed (1) PubMed: 21956185
Uncertain significance (May 20, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000342299.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALPL Number of individuals with the variant: 1 Sex: mixed
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypophosphatasia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000354303.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Likely benign (Feb 15, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000566451.4 First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019	Comment: This variant is associated with the following publications: (PMID: 21956185, 27042741, 30564332, 32803091)
Likely benign (Nov 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002066752.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Uncertain significance (Oct 19, 2022)	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: SCV004174863.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: Further details and the ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/
Benign (Jan 29, 2024)	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: SCV001110181.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Jan 11, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003682748.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 33579333 Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004123405.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: ALPL: BS2 Number of individuals with the variant: 3
Benign (Jan 11, 2020)	no assertion criteria provided Method: clinical testing	Hypophosphatasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001463897.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Likely benign (Feb 02, 2024)	no assertion criteria provided Method: clinical testing	ALPL-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004774190.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Impact of pediatric hypophosphatasia on behavioral health and quality of life.	Pierpont EI	Orphanet journal of rare diseases	2021	PMID: 33579333
Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density.	Nielson CM	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research	2012	PMID: 21956185
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALPL	-	-	-	-

Text-mined citations for rs148405563 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000478.6(ALPL):c.818C>T (p.Thr273Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs148405563 ...