VCV001457572.9 - ClinVar

NM_000478.6(ALPL):c.980T>G (p.Phe327Cys)

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.

(3)

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.980T>G (p.Phe327Cys)

Variation ID: 1457572 Accession: VCV001457572.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.12 1: 21573782 (GRCh38) [ NCBI UCSC ] 1: 21900275 (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	Mar 28, 2022	Jun 17, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000478.6:c.980T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000469.3:p.Phe327Cys	missense
NM_001127501.4:c.815T>G	NP_001120973.2:p.Phe272Cys	missense
NM_001177520.3:c.749T>G	NP_001170991.1:p.Phe250Cys	missense
NM_001369803.2:c.980T>G	NP_001356732.1:p.Phe327Cys	missense
NM_001369804.2:c.980T>G	NP_001356733.1:p.Phe327Cys	missense
NM_001369805.2:c.980T>G	NP_001356734.1:p.Phe327Cys	missense
NC_000001.11:g.21573782T>G
NC_000001.10:g.21900275T>G
NG_008940.1:g.69418T>G

... more HGVS ... less HGVS

Protein change

F272C, F250C, F327C

Other names

Canonical SPDI

NC_000001.11:21573781:T:G

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

Links

dbSNP: rs779832611 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 30, 2023	RCV001972665.4
Osteogenesis imperfecta	Likely pathogenic (1)	criteria provided, single submitter	Jun 14, 2022	RCV002276955.3
Adult hypophosphatasia	Likely pathogenic (1)	criteria provided, single submitter	Mar 26, 2024	RCV003475237.2

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.
Likely pathogenic (Jun 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002564894.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Pathogenic (Oct 30, 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: SCV002247263.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 8954059‚ 9814472‚ 12412800‚ 15660230 Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 327 of the ALPL protein … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 327 of the ALPL protein (p.Phe327Cys). This variant is present in population databases (rs779832611, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of hypophosphatasia (Invitae). This variant is also known as F310C. ClinVar contains an entry for this variant (Variation ID: 1457572). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALPL protein function with a positive predictive value of 95%. This variant disrupts the p.Phe327 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8954059, 9814472, 12412800, 15660230). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adult hypophosphatasia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004195008.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 327 of the ALPL protein (p.Phe327Cys). This variant is present in population databases (rs779832611, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of hypophosphatasia (Invitae). This variant is also known as F310C. ClinVar contains an entry for this variant (Variation ID: 1457572). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALPL protein function with a positive predictive value of 95%. This variant disrupts the p.Phe327 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8954059, 9814472, 12412800, 15660230). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia.	Michigami T	European journal of pediatrics	2005	PMID: 15660230
Function of mutant (G1144A) tissue-nonspecific ALP gene from hypophosphatasia.	Watanabe H	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research	2002	PMID: 12412800
Analysis of localization of mutated tissue-nonspecific alkaline phosphatase proteins associated with neonatal hypophosphatasia using green fluorescent protein chimeras.	Cai G	The Journal of clinical endocrinology and metabolism	1998	PMID: 9814472
Identification of novel missense mutations (Phe310Leu and Gly439Arg) in a neonatal case of hypophosphatasia.	Ozono K	The Journal of clinical endocrinology and metabolism	1996	PMID: 8954059

Text-mined citations for rs779832611 ...

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.980T>G (p.Phe327Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs779832611 ...