rs121918007

chr1-21564139-G-Achr1-21564139-G-Cchr1-21564139-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 12P and 5B. PM1 PM5 PP5_Very_Strong BP4 BS2

The NM_000478.6(ALPL):c.571G>A(p.Glu191Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00141 in 1,614,074 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. E191G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (9 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31 O:1
• Conservation: PhyloP100: 4.64

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21564140-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1455023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 1-21564139-G-A is Pathogenic according to our data. Variant chr1-21564139-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21564139-G-A is described in Lovd as [Pathogenic]. Variant chr1-21564139-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-21564139-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.014826685).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.571G>A	p.Glu191Lys	missense_variant	6/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.571G>A	p.Glu191Lys	missense_variant	6/12	1	NM_000478.6	P1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00244 AC: 613 AN: 251204 Hom.: 4 AF XY: 0.00254 AC XY: 345 AN XY: 135818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00137 AC: 1996 AN: 1461796 Hom.: 9 Cov.: 32 AF XY: 0.00134 AC XY: 976 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0163

Gnomad4 NFE exome AF: 0.000922

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00187 AC: 285 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.00255 AC XY: 190 AN XY: 74458

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0170

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000991 Hom.: 1

Bravo AF: 0.000578

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00257 AC: 312

EpiCase AF: 0.00109

EpiControl AF: 0.00124

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:31 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ALPL: PM3:Very Strong, PM5, PM2:Supporting, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2022	Published functional studies demonstrate that E191K has delayed membrane anchoring (Brun-Heath et al., 2007) and relatively high residual alkaline phosphatase activity (56% and 88% of wildtype), though no dominant negative effect was observed (Zurutuza et al., 1999; Fauvert et al., 2009; Hofmann et al., 2014); Observed in homozygous state in large population cohorts (gnomAD) and in a clinically unaffected adult relative of an individual referred for genetic testing at GeneDx, supporting that this mild variant leads to disease only when a more severe variant is present on the opposite allele (in trans); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24569605, 20739387, 1409720, 19500388, 11855933, 10332035, 18328985, 17719863, 11438998, 12357339, 29659871, 10679946, 19232125, 27920814, 10737975, 29236161, 15671102, 32160374, 31589614, 33083013, 8606878, 33101980, 34213743, 33093890, 33549410) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 191 of the ALPL protein (p.Glu191Lys). This variant is present in population databases (rs121918007, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with hypophosphatasia (PMID: 12357339, 15671102, 24569605). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Glu174Lys. ClinVar contains an entry for this variant (Variation ID: 13670). 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: 1409720, 20739387, 24569605). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 06, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Childhood hypophosphatasia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Feb 18, 2021	The c.571G>A (p.Glu191Lys) variant in the ALPL gene is observed at a minor allele frequency (MAF) of 1.6% in the European (Finnish) population, including 3 homozygous individuals (https://gnomad.broadinstitute.org/variant/1-21890632-G-A). This variant has been reported in multiple individuals affected with autosomal recessive hypophosphatasia and observed to segregate with the disease in family studies (PMID: 12357339, PMID: 24569605). In vitro functional studies have suggested this variant mildly reduced the alkaline phosphatase (ALP) activity (PMID: 24569605). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 13, 2022	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Oct 27, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -

Hypophosphatasia Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 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	Feb 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 10, 2018	The ALPL c.571G>A (p.Glu191Lys) missense variant, also known as p.Glu174Lys, is a well-documented pathogenic variant. It was first identified by Henthorn et al. (1992) in seven out of 46 patients with variable clinical presentation. At least four of these patients were compound heterozygotes for the p.Glu191Lys variant and a second variant, while zygosity was not confirmed in other patients. These patients represented three clinical forms of hypophosphatasia: perinatal (lethal), childhood, and adult and showed autosomal recessive inheritance. Hérasse et al. (2002) reported that the p.Glu191Lys variant is a recurrent variant found in approximately 7% of affected Caucasian chromosomes. In this patient population, the p.Glu191Lys variant was seen in 31% of patients with mild hypophosphatasia (child, adult, and odonto forms). The p.Glu191Lys variant is found at a frequency of 0.01995 in the European (Finnish) population of the Exome Aggregation Consortium. In vitro functional studies performed by Fauvert et al. (2009) showed that the p.Glu191Lys variant has a residual activity of 56% compared to wild type. Based on the collective evidence, the p.Glu191Lys 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, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000478.4:c.571G>A in the ALPL gene has an allele frequency of 0.017 in European(Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that c.571G>A has reduced alkaline phosphatase activity due to structural disturbances and delay in membrane anchoring (PMID:17719863). It was detected in multiple individuals with autosomal recessive hypophosphatasia, compound heterozygous with p.Gly334Asp (PMID: 24569605), c.186G>C (p.M45I) (PMID: 15671102). The patient's phenotype is highly specific for ALPL gene (PMID: 15671102). Co-segregation evidence in a pedigree,one patient was affected and two sister unaffected (PMID:15671102). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MVP, MutationTaster, PrimateAI and REVEL. Phenotype date Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3_Strong; PP1; PP4; PP3. -

Adult hypophosphatasia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Nov 04, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -

Infantile hypophosphatasia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000478.4(ALPL):c.571G>A(E191K, aka E174K) is classified as pathogenic in the context of hypophosphatasia. Sources cited for classification include the following: PMID 25731960, 11438998, 19232125, 10679946, 11855933 and 10332035. Classification of NM_000478.4(ALPL):c.571G>A(E191K, aka E174K) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Osteogenesis imperfecta Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 13, 2021

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.571G>A (p.E191K) alteration is located in exon 6 (coding exon 5) of the ALPL gene. This alteration results from a G to A substitution at nucleotide position 571, causing the glutamic acid (E) at amino acid position 191 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.25% (699/282574) total alleles studied. The highest observed frequency was 1.65% (414/25032) of European (Finnish) alleles. This variant, also described as E174K in literature, is a common founder mutation accounting for up to approximately 10% of disease-causing mutations in the ALPL gene (Hérasse, 2002; Mornet, 2021). This variant has been reported in the heterozygous (Hofmann, 2014; Taillandier, 2018; Mornet, 2021; Ambry internal data) and compound heterozygous (Henthorn, 1992; Schalin-Jäntti, 2010; Hofmann, 2014; Zurutuza, 1999; Mornet, 2021; Sperelakis-Beedham, 2021) states in individuals with hypophosphatasia and low alkaline phosphatase, with the clinical severity correlating with degree of loss of function. This amino acid position is not well conserved in available vertebrate species. Multiple in vitro functional studies using transient expression in cells show slightly reduced activity consistent with a mild loss of function allele based on comparison to wild type and pathogenic controls (Hofmann, 2014; Zurutuza, 1999; Del Angel, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Delayed skeletal maturation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 16, 2021

ACMG categories: PS3,PM1,PP3,PP5,BS1 -

Odontohypophosphatasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

-

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.5	L;.;.;L
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Pathogenic	0.84
Sift	Benign	0.058	T;T;T;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.97	D;.;.;D
Vest4		0.91
MVP		0.95
MPC		1.1
ClinPred		0.084	T
GERP RS		5.2
Varity_R		0.30
gMVP		0.89

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

Other links and lift over

dbSNP: rs121918007; hg19: chr1-21890632;