1-21563219-G-A

Position:

chr1-21563219-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM5PP5_Very_Strong

The NM_000478.6(ALPL):c.407G>A(p.Arg136His) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 4.16

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 12 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000478.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-21563218-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 964572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 1-21563219-G-A is Pathogenic according to our data. Variant chr1-21563219-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21563219-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-21563219-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.407G>A	p.Arg136His	missense_variant	5/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.407G>A	p.Arg136His	missense_variant	5/12	1	NM_000478.6	P1	P05186-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000136

AC:

AN:

250880

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000256

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

163

AN:

1461588

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000132

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 136 of the ALPL protein (p.Arg136His). This variant is present in population databases (rs121918011, gnomAD 0.02%). This missense change has been observed in individuals with hypophosphatasia (PMID: 10094560, 11438998, 11855933, 15694177, 19500388, 25731960, 26783040). This variant is also known as Arg119His. ClinVar contains an entry for this variant (Variation ID: 13675). 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: 10332035, 19500388). This variant disrupts the p.Arg136 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 19500388, 22913777, 24022022), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 24, 2020	The ALPL c.407G>A; p.Arg136His variant (rs121918011), also known as R119H, is reported in the literature in multiple individuals affected with hypophosphatasia, including many individuals who have another pathogenic variant on the opposite chromosome (Brun-Heath 2005, Cui 2012, Mumm 2002, Taillandier 1999, Taillandier 2001, Taillandier 2018, Taketani 2014, Whyte 2012, Whyte 2015). This variant is reported in ClinVar (Variation ID: 13675), and is found in the general population with an overall allele frequency of 0.013% (36/282262 alleles) in the Genome Aggregation Database. The arginine at codon 136 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. However, in vitro functional analyses demonstrate a significant reduction in protein activity (Fauvert 2009). Additionally, other amino acid substitutions at this codon (Cys, Leu, Pro) have been reported in individuals with hypophosphatasia (Cui 2012, Taillandier 2018, Yang 2013). Based on available information, this variant is considered to be pathogenic. References: Brun-Heath I et al. Characterization of 11 novel mutations in the tissue non-specific alkaline phosphatase gene responsible for hypophosphatasia and genotype-phenotype correlations. Mol Genet Metab. 2005 Mar;84(3):273-7. Cui Y et al. A systematic review of genetic skeletal disorders reported in Chinese biomedical journals between 1978 and 2012. Orphanet J Rare Dis. 2012 Aug 22;7:55. 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. Mumm S et al. Denaturing gradient gel electrophoresis analysis of the tissue nonspecific alkaline phosphatase isoenzyme gene in hypophosphatasia. Mol Genet Metab. 2002 Feb;75(2):143-53. Taillandier A et al. Characterization of eleven novel mutations (M45L, R119H, 544delG, G145V, H154Y, C184Y, D289V, 862+5A, 1172delC, R411X, E459K) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with severe hypophosphatasia. Mutations in brief no. 217. Online. Hum Mutat. 1999;13(2):171-2. Taillandier A et al. Twelve novel mutations in the tissue-nonspecific alkaline phosphatase gene (ALPL) in patients with various forms of hypophosphatasia. Hum Mutat. 2001;18(1):83-4. Taillandier A et al. Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metab. 2018 Nov;36(6):723-733. Taketani T et al. Clinical and genetic aspects of hypophosphatasia in Japanese patients. Arch Dis Child. 2014 Mar;99(3):211-5. Whyte MP et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012 Mar 8;366(10):904-13. Whyte MP et al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone. 2015 Jun;75:229-39. Yang H et al. Characterization of six missense mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in Chinese children with hypophosphatasia. Cell Physiol Biochem. 2013;32(3):635-44. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2024	Has also been reported as a single heterozygous variant in association with an odonto form and an adult form of hypophosphatasia (PMID: 19500388, 31707452); Published functional studies demonstrate a damaging effect as protein harboring the R136H variant has approximately 33% of the residual activity of wild-type protein (PMID: 19500388, 10332035); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22913777, 34712267, 34758253, 11438998, 11855933, 11395499, 25023282, 10332035, 28506345, 26783040, 31600233, 31760938, 31707452, 29236161, 15694177, 10094560, 34213743, 34189384, 31589614, 32956941, 33452237, 33549410, 35314707, 35726512, 36444396, 36352425, 32160374, 36708496, 19500388) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Jul 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ALPL: PM1, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting -

Adult hypophosphatasia

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jul 24, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Jun 11, 2024	ACMG Criteria: PS3, PS4, PM1, PM2, PM3, PM5, PP1, PP3, PP4, PP5; Variant was found in heterozygous state. -

Hypophosphatasia

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The ALPL c.407G>A (p.Arg136His) missense variant has been reported in at least seven studies in which it is found in a compound heterozygous state in eight individuals with hypophosphatasia, including two with the infantile form, two with the childhood form, and four with mild symptoms, and in a heterozygous state in two individuals with the adult form of hypophosphatasia. The p.Arg136His variant was also found in a heterozygous state in two asymptomatic parents with low alkaline phosphatase activity and one asymptomatic individual with unknown alkaline phosphatase activity (Taillandier et al. 1998; Taillandier et al. 2001; Mumm et al. 2002; Brun-Heath et al. 2005; Fauvert et al. 2009; Cui et al. 2012; Riancho-Zarrabeitia et al. 2016). The p.Arg136His variant appears to be associated with more severe clinical symptoms when expressed in a compound heterozygous state with an additional ALPL variant. Control data are unavailable for this variant, which is reported at a frequency of 0.00030 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.Arg136His variant protein displays one-third of the activity of the wild type alkaline phosphatase and does not have a dominant-negative effect when co-expressed with the wild type form (Zurutuza et al. 1999; Fauvert et al. 2009). Based on the collective evidence, the p.Arg136His variant is classified as pathogenic for hypophosphatasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 22, 2024	Variant summary: ALPL c.407G>A (p.Arg136His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 250880 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALPL causing Hypophosphatasia (0.00014 vs 0.0035), allowing no conclusion about variant significance. c.407G>A has been reported in the literature as compound heterozygous genotype in multiple individuals affected with autosomal recessive Hypophosphatasia and a fetus with skeletal dysplasia (Taillandier_1999, Okawa_2019, Zhang_2021, del Angel_2020, Bai_2022). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.406C>T, p.Arg136Cys), supporting the critical relevance of codon 136 to ALPL protein function. Two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% residual enzymatic activity of the wild type protein and this variant has also been shown to have a dominant negative effect (Fauvert_2009, del Angel_2020). The following publications have been ascertained in the context of this evaluation (PMID: 36352425, 19500388, 31707452, 31600233, 10094560, 34712267, 32160374). ClinVar contains an entry for this variant (Variation ID: 13675). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 21, 2021	- -

Childhood hypophosphatasia

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 22, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Osteogenesis imperfecta

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 16, 2019

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 09, 2022

- -

Infantile hypophosphatasia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Dec 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.67

D;.;.;D

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.84

.;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.73

D;D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.5

M;.;.;M

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.19

N;N;N;N

REVEL

Pathogenic

0.70

Sift

Benign

0.51

T;T;T;T

Sift4G

Benign

0.51

T;T;T;T

Polyphen

1.0

D;.;.;D

Vest4

0.59

MVP

0.97

MPC

1.4

ClinPred

0.16

GERP RS

4.3

Varity_R

0.11

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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