rs121918008

Positions:

chr1-21575868-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000374840.8(ALPL):c.1133A>T(p.Asp378Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D378H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ALPL
ENST00000374840.8 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 9.22

Variant links:

Genes affected

ALPL (HGNC:438): (alkaline phosphatase, biomineralization associated) This gene encodes a member of the alkaline phosphatase family of proteins. There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue non-specific). The first three are located together on chromosome 2, while the tissue non-specific form is located on chromosome 1. The product of this gene is a membrane bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature enzyme. This enzyme may play a role in bone mineralization. Mutations in this gene have been linked to hypophosphatasia, a disorder that is characterized by hypercalcemia and skeletal defects. [provided by RefSeq, Oct 2015]

ALPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in ENST00000374840.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-21575867-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 1-21575868-A-T is Pathogenic according to our data. Variant chr1-21575868-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 13671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21575868-A-T is described in Lovd as [Pathogenic]. Variant chr1-21575868-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.1133A>T	p.Asp378Val	missense_variant	10/12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.1133A>T	p.Asp378Val	missense_variant	10/12	1	NM_000478.6	ENSP00000363973	P1	P05186-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251492

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2022	Reported as the most common ALPL variant identified in American HPP cohorts, with phenotypic severity ranging from odonto HPP to severe childhood HPP (Whyte et al., 2015); Published functional studies demonstrate a dominant negative effect (Del Angel et al., 2020; Muller et al., 2000; Fauvert et al., 2009); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20301329, 19335222, 17213282, 28580391, 12162492, 32160374, 33069919, 8606878, 33549410, 30215116, 28401263, 19500388, 10690885, 1409720, 25731960) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 22, 2023	The ALPL c.1133A>T; p.Asp378Val variant (rs121918008) has been well-studied and is capable of causing hypophosphatasia in the heterozygous state (Fauvert 2009, Henthorn 1992, Whyte 2007). It has been shown to segregate with the disease in multiple large pedigrees (Henthorn 1992, Moore 1999, Muller 2000), and described as a common cause of the disease, particularly among Caucasians in America (Camacho 2016, Whyte 2007). Functional studies in bacterial and mammalian cells have demonstrated that this is a loss of function variant, probably due to the location of the affected residue near an important zinc-binding site, and that it exerts a dominant negative effect when co-expressed with wild-type protein (Fauvert 2009, Lia-Baldini 2001, Muller 2000, Whyte 2007). Two other variants affecting this codon, Asp378Gly and Asp378His, have also been reported in HPP patients (Tenorio 2017, Wenkert 2011). This variant is listed in the ClinVar Database (Variation ID: 13671) and in the Genome Aggregation Database with an overall population frequency of 0.0004% (identified on 1 out of 251,492 chromosomes), indicating it is not a common polymorphism. Based on the available information, the p.Asp378Val variant is classified as pathogenic. References: Camacho PM et al. Adult Hypophosphatasia Treated With Teriparatide: Report Of 2 Patients And Review Of The Literature. Endocr Pract. 2016 Aug;22(8):941-50. PMID: 27042741. Fauvert D et al. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC Med Genet. 2009 Jun 6;10:51. PMID: 19500388. Henthorn PS et al. Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9924-8. PMID: 1409720. Lia-Baldini AS et al. A molecular approach to dominance in hypophosphatasia. Hum Genet. 2001 Jul;109(1):99-108. PMID: 11479741. Tenorio J et al. Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia. Am J Med Genet A. 2017 Mar;173(3):601-610. PMID: 28127875. Moore CA et al. Mild autosomal dominant hypophosphatasia: in utero presentation in two families. Am J Med Genet. 1999 Oct 29;86(5):410-5. PMID: 10508980. Muller HL et al. Asp361Val Mutant of alkaline phosphatase found in patients with dominantly inherited hypophosphatasia inhibits the activity of the wild-type enzyme. J Clin Endocrinol Metab. 2000 Feb;85(2):743-7. PMID: 10690885. Wenkert D et al. Hypophosphatasia: nonlethal disease despite skeletal presentation in utero (17 new cases and literature review). J Bone Miner Res. 2011 Oct;26(10):2389-98. PMID: 21713987. Whyte MP et al. Adult hypophosphatasia treated with teriparatide. J Clin Endocrinol Metab. 2007 Apr;92(4):1203-8. PMID: 17213282. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 378 of the ALPL protein (p.Asp378Val). This variant is present in population databases (rs121918008, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant and recessive hypophosphatasia (PMID: 1409720, 10508980, 17213282, 17922851, 19335222, 19500388, 21713987, 25731960, 28580391). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asp361Val. ClinVar contains an entry for this variant (Variation ID: 13671). 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%. Experimental studies have shown that this missense change affects ALPL function (PMID: 19500388). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2014	- -

Hypophosphatasia

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 18, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 03, 2017	Variant summary: The ALPL c.1133A>T (p.Asp378Val) variant, alternatively also known as Asp361Val, involves the alteration of a conserved nucleotide, is located in alkaline phosphatase domain of the protein (InterPro) and is predicted to be damaging by 4/4 in silico tools (SNPs&GO not captured here due to low reliability index value). The variant of interest was not observed in controls (ExAC, 1000 Gs, ESP, or publication controls). This variant is widely reported as a pathogenic variant with consistent genotype-phenotype and functional studies. The variant is mainly found in Caucasian HPP patients and is most prevalent in North American patient cohorts (Whyte_2015). The variant has been presented in affected individuals in both autosomal dominant and recessive manners of inheritance. When the variant is dominantly inherited, it usually causes a mild phenotype, while the recessive mode causes a more severe phenotype. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as Pathogenic. -

Infantile hypophosphatasia

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2007	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 21, 2015	- -

Adult hypophosphatasia

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 21, 2023	- -

ALPL-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2024

The ALPL c.1133A>T variant is predicted to result in the amino acid substitution p.Asp378Val. This variant has been reported to be causative for hypophosphatasia (HPP) (reported as c.1309A>T p.Asp361Val, Henthorn et al. 1992. PubMed ID: 1409720; Fauvert et al. 2009. PubMed ID: 19500388; Whyte et al. 2007. PubMed ID: 17213282; Table S2, Del Angel et al. 2020. PubMed ID: 32160374). In addition, other variants affecting the same amino acid (p.Asp378His, p.Asp378Gly, and p.Asp378Tyr) were reported to be causative (Human Gene Mutation Database - HGMD; https://alplmutationdatabase.jku.at/table/). Functional studies suggest that the p.Asp378Val variant (also referred to as p.Asp361Val) has a dominant negative effect and led to reduced enzyme activity (Lia-Baldini et al. 2001. PubMed ID: 11479741; Fauvert et al. 2009 PubMed ID: 19500388; https://alplmutationdatabase.jku.at/table/). In summary, we classify this variant as pathogenic. -

Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 28, 2021

- -

Childhood hypophosphatasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

The c.1133A>T variant is the most common alteration reported in probands with hypophosphatasia from the United States (PMID: 25731960). This amino acid change results in the replacement of a highly conserved aspartic acid with valine at codon 378 of the ALPL protein (p.Asp378Val). In vitro studies demonstrate that this variant exerts a dominant negative affect on alkaline phosphatase activity (PMID: 19500388). Additionally, this variant has been shown to segregate with autosomal dominant hypophosphatasia in many families (PMID: 10508980, PMID: 19335222, PMID: 21713987) and has been reported in the heterozygous state in many individuals affected with mild to severe childhood or adult hypophosphatasia (PMID: 19500388, PMID: 21713987, PMID: 17213282, PMID: 28580391). This variant has been reported in trans with another variant in two individuals with severe forms of the disease (PMID: 1409720, PMID: 17922851). This variant is rare to absent in population databases (gnomAD frequency of 3.98x10^-6). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.99

D;.;.;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

1.0

D;D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.8

H;.;.;H

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-8.5

D;D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

1.0

MutPred

0.96

Loss of sheet (P = 0.0483);.;.;Loss of sheet (P = 0.0483);

MVP

0.99

MPC

1.5

ClinPred

1.0

GERP RS

4.9

Varity_R

0.97

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over