NM_000026.4(ADSL):c.1315C>T (p.Gln439Ter) AND Adenylosuccinate lyase deficiency

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 20, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003499624.3

Allele description [Variation Report for NM_000026.4(ADSL):c.1315C>T (p.Gln439Ter)]

NM_000026.4(ADSL):c.1315C>T (p.Gln439Ter)

Gene:

ADSL:adenylosuccinate lyase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q13.1

Genomic location:

Preferred name:

NM_000026.4(ADSL):c.1315C>T (p.Gln439Ter)

HGVS:

NC_000022.11:g.40365003C>T
NG_007993.2:g.23504C>T
NM_000026.3:c.1315C>T
NM_000026.4:c.1315C>TMANE SELECT
NM_001123378.3:c.1191+638C>T
NM_001317923.2:c.1123C>T
NM_001363840.3:c.1315C>T
NM_001410812.1:c.1315C>T
NM_001410814.1:c.1270C>T
NM_001410816.1:c.1191+638C>T
NP_000017.1:p.Gln439Ter
NP_001304852.1:p.Gln375Ter
NP_001350769.1:p.Gln439Ter
NP_001397741.1:p.Gln439Ter
NP_001397743.1:p.Gln424Ter
NC_000022.10:g.40761007C>T
NR_134256.2:n.1405C>T

Protein change:

Q375*

Molecular consequence:

NM_001123378.3:c.1191+638C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001410816.1:c.1191+638C>T - intron variant - [Sequence Ontology: SO:0001627]
NR_134256.2:n.1405C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000026.4:c.1315C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001317923.2:c.1123C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001363840.3:c.1315C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001410812.1:c.1315C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001410814.1:c.1270C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Adenylosuccinate lyase deficiency (ADSLD)
Identifiers:: MONDO: MONDO:0007068; MedGen: C0268126; Orphanet: 46; OMIM: 103050

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004282761	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 23, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10888601, 20177786, 28492532
SCV005086347	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 20, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12368987, 20127976, 22180458, 24781210, 28487569, 33648541, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004282761

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 23, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV005086347

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 20, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Hartmannová H, Stibůrková B, Krijt J, Zikánová M, Sebesta I.

Hum Mol Genet. 2000 Jun 12;9(10):1501-13.

PubMed [citation]

PMID:: 10888601

Adenylosuccinate lyase deficiency in a Malaysian patient, with novel adenylosuccinate lyase gene mutations.

Chen BC, McGown IN, Thong MK, Pitt J, Yunus ZM, Khoo TB, Ngu LH, Duley JA.

J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S159-62. doi: 10.1007/s10545-010-9056-z. Epub 2010 Feb 23.

PubMed [citation]

PMID:: 20177786

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004282761.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with ADSL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln439*) in the ADSL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADSL are known to be pathogenic (PMID: 10888601, 20177786).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086347.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with adenylosuccinase deficiency, (MIM#103050). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0601 - Variant results in the truncation of part of the well-established functional ADSL_C domain. Multiple missense variants and two small inframe deletions within this truncated region have been reported in affected individuals. At least two of these variants have functional evidence supporting the importance of this region in protein function (DECIPHER, PMID: 28487569, PMID: 20127976, PMID: 22180458, PMID: 24781210, PMID: 12368987, PMID: 33648541). (SP) 0710 - Other protein truncating variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. These variants have been reported twice as VUSs with no clinical information (ClinVar). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (p.(Arg190Gly)) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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