ClinVar Genomic variation as it relates to human health
NM_000026.4(ADSL):c.1277G>A (p.Arg426His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000026.4(ADSL):c.1277G>A (p.Arg426His)
Variation ID: 2462 Accession: VCV000002462.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.1 22: 40364965 (GRCh38) [ NCBI UCSC ] 22: 40760969 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 13, 2015 May 1, 2024 Jan 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000026.4:c.1277G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000017.1:p.Arg426His missense NM_001123378.3:c.1191+600G>A intron variant NM_001317923.2:c.1085G>A NP_001304852.1:p.Arg362His missense NM_001363840.3:c.1277G>A NP_001350769.1:p.Arg426His missense NR_134256.2:n.1367G>A non-coding transcript variant NC_000022.11:g.40364965G>A NC_000022.10:g.40760969G>A NG_007993.2:g.23466G>A P30566:p.Arg426His - Protein change
- R426H, R362H
- Other names
- p.R426H:CGT>CAT
- Canonical SPDI
- NC_000022.11:40364964:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00022
The Genome Aggregation Database (gnomAD) 0.00024
Exome Aggregation Consortium (ExAC) 0.00026
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ADSL | - | - |
GRCh38 GRCh37 |
- | 867 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Jan 23, 2024 | RCV000002566.37 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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May 16, 2022 | RCV000186693.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 2, 2021 | RCV002512680.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 16, 2014)
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criteria provided, single submitter
Method: clinical testing
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Adenylosuccinase deficiency
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000246324.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Adenylosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000438687.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The ADSL c.1277G>A (p.Arg426His) variant has been identified in a homozygous state in 13 individuals with adenylosuccinase deficiency, in a compound heterozygous state in four … (more)
The ADSL c.1277G>A (p.Arg426His) variant has been identified in a homozygous state in 13 individuals with adenylosuccinase deficiency, in a compound heterozygous state in four individuals, and in a heterozygous state in six unaffected family members (Marie et al. 1999; Kmoch et al. 2000; Edery et al. 2003; Jurecka et al. 2008; Donti et al. 2016). The p.Arg426His variant was absent from 88 controls and is reported at a frequency of 0.00042 in the European (non-Finnish) population of the Exome Aggregation Consortium. In vitro functional studies demonstrated that the p.Arg426His mutant enzyme resulted in approximately 50% of wild type activity. Biochemical analyses showed that the p.Arg426His variant produced an unstable protein (Kmoch et al. 2000; Jurecka et al. 2008; Zikanova et al. 2010). Based on the collective evidence, the p.Arg426His variant is classified as pathogenic for adenylosuccinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Sep 12, 2017)
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criteria provided, single submitter
Method: clinical testing
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Adenylosuccinate lyase deficiency
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000713087.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Arg426His (NM_000026.2 c.1277G>A) variant in ADSL has been reported in 11 homozygotes and 9 compound heterozygous individuals with Adenylosuccinate lyase deficiency (ADSL) (Cantwell 1988, … (more)
The p.Arg426His (NM_000026.2 c.1277G>A) variant in ADSL has been reported in 11 homozygotes and 9 compound heterozygous individuals with Adenylosuccinate lyase deficiency (ADSL) (Cantwell 1988, Marie 1999, Kmoch 2000, Mouchegh 2007, Jurecka 2008, Lundy 2010, Henneke 2010, Jurecka 2016 and Donti 2016), and segregated in 3 family members in 2 families (Edery 2003 Donti 2016), and has been reported i n ClinVar (Variation ID#2462) by multiple laboratories as pathogenic. In vitro f unctional studies provide evidence supporting an impact on protein function (Bar esova 2012 and Zikanova 2010). This variant has been identified in 0.042% (28/66 ,740) of European chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs119450941). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets criteria to be class ified as pathogenic for ADSL in an autosomal recessive manner based upon biallel ic case observations, segregation in affected individuals and functional evidenc e. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Adenylosuccinate lyase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440379.2
First in ClinVar: Oct 30, 2020 Last updated: Nov 04, 2023 |
Comment:
Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3
Clinical Features:
Scoliosis (present) , Focal-onset seizure (present) , Cerebellar ataxia (present) , Severe global developmental delay (present)
Sex: male
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Pathogenic
(Jun 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Adenylosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023025.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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Adenylosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000631362.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 426 of the ADSL protein (p.Arg426His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 426 of the ADSL protein (p.Arg426His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with adenylosuccinate lyase deficiency (PMID: 10090474, 12833398, 16839792, 18524658, 25112391, 27504266). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2462). 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 ADSL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADSL function (PMID: 18524658, 20127976). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003677029.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1277G>A (p.R426H) alteration is located in exon 12 (coding exon 12) of the ADSL gene. This alteration results from a G to A substitution … (more)
The c.1277G>A (p.R426H) alteration is located in exon 12 (coding exon 12) of the ADSL gene. This alteration results from a G to A substitution at nucleotide position 1277, causing the arginine (R) at amino acid position 426 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the ADSL c.1277G>A alteration was observed in 0.02% (51/282896) of total alleles studied, with a frequency of 0.03% (42/129196) in the European (non-Finnish) subpopulation. This mutation is the most common mutation occurring in about 30% of affected individuals; it has been identified in the homozygous and compound heterozygous state in multiple individuals with adenylosuccinase deficiency (Ray, 2013; Jurecka, 2014; Donti, 2016; Mastrogiorgio, 2021). In vitro analysis demonstrated reduced thermal stability and ADSL activity (Kmoch, 2000; Zikanova, 2010). The p.R426H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Dec 28, 2013)
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criteria provided, single submitter
Method: clinical testing
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Adenylosuccinase deficiency
Affected status: unknown
Allele origin:
germline
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Courtagen Diagnostics Laboratory, Courtagen Life Sciences
Accession: SCV000236505.2
First in ClinVar: Jul 02, 2015 Last updated: Jul 13, 2015 |
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Pathogenic
(Jan 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511432.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Nov 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000840712.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Jun 26, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000225471.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 5
Sex: mixed
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Adenylosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894269.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Mar 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
paternal
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Laboratoire Génétique Moléculaire, CHRU TOURS
Accession: SCV001760573.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
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Pathogenic
(Jun 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502280.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(May 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000240259.16
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate reduced enzyme activity (Jurecka et al., 2008; Ray et al., 2013; Zikanova et al., 2010); In silico analysis supports that this … (more)
Published functional studies demonstrate reduced enzyme activity (Jurecka et al., 2008; Ray et al., 2013; Zikanova et al., 2010); 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: 20127976, 29655203, 31164858, 10958654, 23714113, 10888601, 10090474, 7334371, 18524658, 16839792, 23504561, 27504266, 12833398, 30609409, 31729379, 34426522, 34582790, 33497949, 31589614, 33648541) (less)
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Pathogenic
(Aug 01, 2008)
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no assertion criteria provided
Method: literature only
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ADENYLOSUCCINASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022724.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 13, 2015 |
Comment on evidence:
In an infant in which epilepsy was the first manifestation of adenylosuccinase deficiency (ADSLD; 103050), Maaswinkel-Mooij et al. (1997) reported homozygosity for an arg401-to-his (R401H) … (more)
In an infant in which epilepsy was the first manifestation of adenylosuccinase deficiency (ADSLD; 103050), Maaswinkel-Mooij et al. (1997) reported homozygosity for an arg401-to-his (R401H) substitution in the ADSL gene. Marie et al. (1999) found 5 apparently unrelated patients with adenylosuccinate lyase deficiency who had an arg426-to-his (R426H) mutation, which had previously been identified as R401H by Maaswinkel-Mooij et al. (1997). The discrepancy in the numbering system was due to the finding by Marie et al. (1999) that the cDNA of human ADSL encodes a protein of 484 rather than 459 amino acids. The authors noted that 426H mutation was the most frequent one identified to that time, accounting for 12 of the 34 alleles investigated. Kmoch et al. (2000) described a patient with ADSLD who was homozygous for the R426H mutation. Edery et al. (2003) observed an unusually variable combination of clinical features and striking intrafamilial variability in the phenotype. Among 3 sibs from a family originally from Portugal, the proband had marked psychomotor regression and progressive cerebellar vermis atrophy; the other 2 affected sibs presented mainly autistic features. The sibs were homozygous for the R426H mutation. The authors suggested that, in any patient with mental retardation of unexplained origin, adenylosuccinate lyase deficiency should be considered and assessed using a simple urinary screening method for the presence of succinylpurines. Jurecka et al. (2008) identified homozygosity for the R426H mutation in 2 unrelated Polish patients with ADSL deficiency. One had a severe form of the disorder with severe psychomotor retardation, inability to walk, and refractory seizures, and was bedridden by age 9.5. The other had a relatively less severe phenotype and could sit and walk a few steps at age 4.5 years. Two additional unrelated Polish patients were compound heterozygous for the R426H allele and another pathogenic mutation in the ADSL gene. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809533.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966107.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical and molecular characterization of patients with adenylosuccinate lyase deficiency. | Mastrogiorgio G | Orphanet journal of rare diseases | 2021 | PMID: 33648541 |
Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy. | Demos M | Frontiers in neurology | 2019 | PMID: 31164858 |
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. | Ceyhan-Birsoy O | American journal of human genetics | 2019 | PMID: 30609409 |
Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. | Lindy AS | Epilepsia | 2018 | PMID: 29655203 |
Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design. | Chitty JL | The Journal of biological chemistry | 2017 | PMID: 28559277 |
Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines. | Mao X | Scientific reports | 2017 | PMID: 28487569 |
Diagnosis of adenylosuccinate lyase deficiency by metabolomic profiling in plasma reveals a phenotypic spectrum. | Donti TR | Molecular genetics and metabolism reports | 2016 | PMID: 27504266 |
Adenylosuccinate lyase deficiency. | Jurecka A | Journal of inherited metabolic disease | 2015 | PMID: 25112391 |
Attenuated adenylosuccinate lyase deficiency: a report of one case and a review of the literature. | Jurecka A | Neuropediatrics | 2014 | PMID: 23504561 |
Inherent properties of adenylosuccinate lyase could explain S-Ado/SAICAr ratio due to homozygous R426H and R303C mutations. | Ray SP | Biochimica et biophysica acta | 2013 | PMID: 23714113 |
Mutations of ATIC and ADSL affect purinosome assembly in cultured skin fibroblasts from patients with AICA-ribosiduria and ADSL deficiency. | Baresova V | Human molecular genetics | 2012 | PMID: 22180458 |
Adenylosuccinate lyase deficiency in the United Kingdom pediatric population: first three cases. | Lundy CT | Pediatric neurology | 2010 | PMID: 20933180 |
In vivo proton MR spectroscopy findings specific for adenylosuccinate lyase deficiency. | Henneke M | NMR in biomedicine | 2010 | PMID: 20175147 |
Biochemical and structural analysis of 14 mutant adsl enzyme complexes and correlation to phenotypic heterogeneity of adenylosuccinate lyase deficiency. | Zikanova M | Human mutation | 2010 | PMID: 20127976 |
Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency. | Jurecka A | Molecular genetics and metabolism | 2008 | PMID: 18524658 |
Lethal fetal and early neonatal presentation of adenylosuccinate lyase deficiency: observation of 6 patients in 4 families. | Mouchegh K | The Journal of pediatrics | 2007 | PMID: 17188615 |
Adenylosuccinate lyase deficiency. | Spiegel EK | Molecular genetics and metabolism | 2006 | PMID: 16839792 |
Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: a report on three patients. | Edery P | American journal of medical genetics. Part A | 2003 | PMID: 12833398 |
Human adenylosuccinate lyase (ADSL), cloning and characterization of full-length cDNA and its isoform, gene structure and molecular basis for ADSL deficiency in six patients. | Kmoch S | Human molecular genetics | 2000 | PMID: 10888601 |
Mutation analysis in adenylosuccinate lyase deficiency: eight novel mutations in the re-evaluated full ADSL coding sequence. | Marie S | Human mutation | 1999 | PMID: 10090474 |
Adenylosuccinase deficiency presenting with epilepsy in early infancy. | Maaswinkel-Mooij PD | Journal of inherited metabolic disease | 1997 | PMID: 9266401 |
In vitro release of endogenous amino acids from granule cell-, stellate cell-, and climbing fiber-deficient cerebella. | Flint RS | Journal of neurochemistry | 1981 | PMID: 7334371 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ADSL | - | - | - | - |
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Text-mined citations for rs119450941 ...
HelpRecord last updated Jun 23, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.