rs119450941
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000026.4(ADSL):c.1277G>A(p.Arg426His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000026.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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ADSL | ENST00000623063.3 | c.1277G>A | p.Arg426His | missense_variant | Exon 12 of 13 | 1 | NM_000026.4 | ENSP00000485525.1 | ||
ENSG00000284431 | ENST00000639722.1 | n.*973G>A | non_coding_transcript_exon_variant | Exon 11 of 31 | 5 | ENSP00000492828.1 | ||||
ENSG00000284431 | ENST00000639722.1 | n.*973G>A | 3_prime_UTR_variant | Exon 11 of 31 | 5 | ENSP00000492828.1 |
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000199 AC: 50AN: 251490Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135920
GnomAD4 exome AF: 0.000273 AC: 399AN: 1461788Hom.: 0 Cov.: 31 AF XY: 0.000283 AC XY: 206AN XY: 727198
GnomAD4 genome AF: 0.000223 AC: 34AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74306
ClinVar
Submissions by phenotype
Adenylosuccinate lyase deficiency Pathogenic:11
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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. -
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The observed missense c.1277G>A (p.Arg426His) variant in ADSL gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with adenylosuccinase deficiency (Ray et al., 2013; Jurecka et al., 2014; Donti et al., 2016; Mastrogiorgio et al., 2021). It has also been observed to segregate with disease in related individuals. Experimental analysis demonstrated this variant to cause reduced thermal stability and ADSL activity (Kmoch et al., 2000; Zikanova et al., 2010). This variant is present with allele frequency of 0.02% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg426His in ADSL is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 426 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: ADSL c.1277G>A (p.Arg426His) results in a non-conservative amino acid change located in the Adenylosuccinate lyase C-terminal domain (IPR019468) of 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 0.0002 in 251490 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ADSL causing Adenylosuccinate Lyase Deficiency, allowing no conclusion about variant significance. c.1277G>A has been reported in the literature in multiple hompozygous and compound heterozygous individuals affected with Adenylosuccinate Lyase Deficiency (Edery_2003, Mouchegh_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12833398, 17188615). ClinVar contains an entry for this variant (Variation ID: 2462). Based on the evidence outlined above, the variant was classified as pathogenic. -
Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3 -
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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. -
not provided Pathogenic:9
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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) -
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ADSL: PM3:Very Strong, PM2, PM5, PP4 -
Inborn genetic diseases Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at