rs371243939
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000478.6(ALPL):c.1171C>T(p.Arg391Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000582 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R391H) has been classified as Pathogenic.
Frequency
Consequence
NM_000478.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALPL | NM_000478.6 | c.1171C>T | p.Arg391Cys | missense_variant | 10/12 | ENST00000374840.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALPL | ENST00000374840.8 | c.1171C>T | p.Arg391Cys | missense_variant | 10/12 | 1 | NM_000478.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251468Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135912
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.0000646 AC XY: 47AN XY: 727248
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74374
ClinVar
Submissions by phenotype
Hypophosphatasia Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 19, 2024 | Variant summary: ALPL c.1171C>T (p.Arg391Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 1614092 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ALPL causing Hypophosphatasia (5.8e-05 vs 0.0035), allowing no conclusion about variant significance. c.1171C>T has been reported in the literature in multiple compound heterozygous individuals affected with Hypophosphatasia (examples: Zurutuza_1999, Simon-Bouy_2008, Whyte_2012, and DelAngel_2020). These data indicate that the variant is very likely to be associated with disease. Multiple reports have shown experimental evidence that this variant affects normal protein function (examples: Zurutuza_1999, DelAngel_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 25731960, 22397652, 18925618, 10332035). ClinVar contains an entry for this variant (Variation ID: 550442). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 391 of the ALPL protein (p.Arg391Cys). This variant is present in population databases (rs371243939, gnomAD 0.003%). This missense change has been observed in individual(s) with ALPL-related conditions (PMID: 10332035, 17719863, 22397652, 29159075, 29354166). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg374Cys. ClinVar contains an entry for this variant (Variation ID: 550442). 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, 17719863, 19500388). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 04, 2023 | Also denoted as R374C due to alternative nomenclature; Published functional studies demonstrate a damaging effect with reduced alkaline phosphatase activity (Zurutuza et al., 1999; Fauvert et al., 2009; Del Angel et al., 2020); Not observed at 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: 18523927, 34662886, 28530318, 17719863, 19500388, 29159075, 15300736, 10332035, 29354166, 29236161, 32160374, 22397652) - |
Osteogenesis imperfecta Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 18, 2022 | - - |
Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 08, 2022 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2024 | The c.1171C>T (p.R391C) alteration is located in exon 10 (coding exon 9) of the ALPL gene. This alteration results from a C to T substitution at nucleotide position 1171, causing the arginine (R) at amino acid position 391 to be replaced by a cysteine (C)._x000D_ _x000D_ for loss of function ALPL-related hypophosphatasia; however, its clinical significance for dominant negative ALPL-related hypophosphatasia is uncertain. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (3/251468) total alleles studied. The highest observed frequency was 0.003% (3/113748) of European (non-Finnish) alleles. This variant has been identified likely in trans with another ALPL variant in multiple individuals diagnosed with reduced ALP serum levels and teeth/skeletal abnormalities (Brun-Heath, 2007; Costain, 2018; Lawrence, 2017). Additionally, this variant has been reported as homozygous in one individual with infantile hypophosphatasia (Del Angel, 2020). Furthermore, this variant has been reported heterozygous in individuals with varying levels of severity of hypophosphatasia (Fauvert, 2009; Taillandier, 2018; Gurevich, 2020; Lefever, 2020; Vogt, 2020). Another alteration at the same codon, c.1172G>A (p.R391H), has been detected in one individual with odontohypophosphatasia form of hypophosphatasia (Fauvert, 2009). This amino acid position is highly conserved in available vertebrate species. Multiple assays showed this variant results in significant reduction in ALPL activity (Zurutuza, 1999; Fauvert, 2009; 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. - |
Infantile hypophosphatasia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 17, 2017 | - - |
Adult hypophosphatasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 26, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at