rs119450941

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP3_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R426C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

ADSL
NM_000026.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:22

Conservation

PhyloP100: 8.88

Publications

28 publications found

Variant links:

Genes affected

ADSL (HGNC:291): (adenylosuccinate lyase) The protein encoded by this gene belongs to the lyase 1 family. It is an essential enzyme involved in purine metabolism, and catalyzes two non-sequential reactions in the de novo purine biosynthetic pathway: the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazole carboxamide ribotide (AICAR) and the conversion of adenylosuccinate (S-AMP) to adenosine monophosphate (AMP). Mutations in this gene are associated with adenylosuccinase deficiency (ADSLD), a disorder marked with psychomotor retardation, epilepsy or autistic features. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

ADSL Gene-Disease associations (from GenCC):

adenylosuccinate lyase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ADSL links:

ENSG00000284431 (HGNC:):

ENSG00000284431 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000026.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-40364964-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204798.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

PP5

Variant 22-40364965-G-A is Pathogenic according to our data. Variant chr22-40364965-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADSL	NM_000026.4 link	c.1277G>A	p.Arg426His	missense_variant	Exon 12 of 13	ENST00000623063.3	NP_000017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ADSL	ENST00000623063.3 link	c.1277G>A	p.Arg426His	missense_variant	Exon 12 of 13	1	NM_000026.4	ENSP00000485525.1
ENSG00000284431	ENST00000639722.1 link	n.*973G>A		non_coding_transcript_exon_variant	Exon 11 of 31	5		ENSP00000492828.1
ENSG00000284431	ENST00000639722.1 link	n.*973G>A		3_prime_UTR_variant	Exon 11 of 31	5		ENSP00000492828.1

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000199

AC:

AN:

251490

AF XY:

0.000199

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000360

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000273

AC:

399

AN:

1461788

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

206

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000333

AC:

370

AN:

1111912

Other (OTH)

AF:

0.000248

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000223

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000342

Hom.:

Bravo

AF:

0.000215

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Adenylosuccinate lyase deficiency

Pathogenic:12

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 14, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3 -

Aug 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 28, 2013

Courtagen Diagnostics Laboratory, Courtagen Life Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 12, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 16, 2014

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 31, 2023

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_strong;PS4_strong;PM2_supporting;PM3_moderate;PP1_supporting;PP4_supporting -

not provided

Pathogenic:9

Jun 17, 2020

AiLife Diagnostics, AiLife Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 28, 2017

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 31, 2021

Laboratoire Génétique Moléculaire, CHRU TOURS

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 26, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADSL: PM3:Very Strong, PM2, PM5, PP4 -

Inborn genetic diseases

Pathogenic:1

Aug 02, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;T;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

M;.;.

PhyloP100

8.9

PrimateAI

Uncertain

0.59

REVEL

Pathogenic

0.90

Sift4G

Uncertain

0.046

D;.;D

Polyphen

0.46

P;.;.

Vest4

0.87

MVP

0.86

MPC

0.45

ClinPred

0.80

GERP RS

5.7

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.95

gMVP

0.85

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over