ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.571G>A (p.Glu191Lys) (rs121918007)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000224962 SCV000231547 pathogenic not provided 2016-04-13 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224962 SCV000280679 pathogenic not provided 2016-05-06 criteria provided, single submitter clinical testing
GeneDx RCV000224962 SCV000617526 pathogenic not provided 2017-07-06 criteria provided, single submitter clinical testing The E191K variant in the ALPL gene has been reported previously in multiple individuals with hypophosphatasia, including the infantile, childhood, and adult types, when in trans with another disease-causing variant (Henthorn et al., 1992; Schalin-Jäntti et al., 2010; Hofmann et al., 2014). The E191K variant is observed in 131/6568 (2.0%) alleles from individuals of Finnish European background, and in 175/66400 (0.27%) alleles from individuals of non-Finnish European background, including 1 homozygous individual, in the ExAC dataset (Lek et al., 2016). The E191K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species. Functional studies demonstrate that E174K has reduced alkaline phosphatase activity due to structural disturbances and delay in membrane anchoring (Brun-Heath et al., 2007). We interpret E191K as a pathogenic variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224962 SCV000692612 likely pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000207183 SCV000696802 pathogenic Hypophosphatasia 2016-02-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763300 SCV000893965 pathogenic Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000207183 SCV000914390 pathogenic Hypophosphatasia 2018-12-10 criteria provided, single submitter clinical testing 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.
Invitae RCV000224962 SCV000950872 pathogenic not provided 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces glutamate with lysine at codon 191 of the ALPL protein (p.Glu191Lys). The glutamate residue is moderately conserved and there is a small physicochemical difference between glutamate and lysine. This variant is present in population databases (rs121918007, ExAC 2.0%). This variant has been reported in individuals affected with hypophosphatasia and observed to segregate with the disease in family studies (PMID: 12357339, 15671102, 24569605). This variant is also known as p.Glu174Lys in the literature. ClinVar contains an entry for this variant (Variation ID: 13670). Experimental studies have shown that this missense change affects ALPL protein function in vitro (PMID: 20739387, 1409720, 24569605). For these reasons, this variant has been classified as Pathogenic.
Myriad Women's Health, Inc. RCV000014658 SCV001193949 pathogenic Infantile hypophosphatasia 2019-11-12 criteria provided, single submitter clinical testing 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.
Centogene AG - the Rare Disease Company RCV001250150 SCV001424359 pathogenic Odontohypophosphatasia criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000014659 SCV001439987 pathogenic Childhood hypophosphatasia 2019-01-01 criteria provided, single submitter clinical testing
OMIM RCV000014658 SCV000034913 pathogenic Infantile hypophosphatasia 2002-10-01 no assertion criteria provided literature only
OMIM RCV000014659 SCV000034914 pathogenic Childhood hypophosphatasia 2002-10-01 no assertion criteria provided literature only
OMIM RCV000014660 SCV000034915 pathogenic Adult hypophosphatasia 2002-10-01 no assertion criteria provided literature only
GeneReviews RCV000207183 SCV000262613 pathogenic Hypophosphatasia 2016-02-04 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000014659 SCV000536856 likely pathogenic Childhood hypophosphatasia 2015-10-27 no assertion criteria provided research
Reproductive Health Research and Development,BGI Genomics RCV000207183 SCV001142293 pathogenic Hypophosphatasia 2020-01-06 no assertion criteria provided curation 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.
Natera, Inc. RCV000207183 SCV001459879 pathogenic Hypophosphatasia 2020-09-16 no assertion criteria provided clinical testing

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