NM_000026.4(ADSL):c.1355G>A (p.Arg452His) AND Adenylosuccinate lyase deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 19, 2024
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:: RCV000634538.8

Allele description [Variation Report for NM_000026.4(ADSL):c.1355G>A (p.Arg452His)]

NM_000026.4(ADSL):c.1355G>A (p.Arg452His)

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.1355G>A (p.Arg452His)

HGVS:

NC_000022.11:g.40365043G>A
NG_007993.2:g.23544G>A
NM_000026.4:c.1355G>AMANE SELECT
NM_001123378.3:c.1191+678G>A
NM_001317923.2:c.1163G>A
NM_001363840.3:c.1355G>A
NP_000017.1:p.Arg452His
NP_001304852.1:p.Arg388His
NP_001350769.1:p.Arg452His
NC_000022.10:g.40761047G>A
NM_000026.2:c.1355G>A
NR_134256.2:n.1445G>A

Protein change:

R388H

Links:

dbSNP: rs775671027

NCBI 1000 Genomes Browser:

rs775671027

Molecular consequence:

NM_001123378.3:c.1191+678G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000026.4:c.1355G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001317923.2:c.1163G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363840.3:c.1355G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_134256.2:n.1445G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

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

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protein Jade-3 [Homo sapiens]
protein Jade-3 [Homo sapiens]
gi|7662006|ref|NP_055550.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000755856	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 19, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002099038	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Mar 5, 2021)	inherited	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000755856

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 19, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002099038

New York Genome Center - CSER-NYCKidSeq

criteria provided, single submitter

(NYGC Assertion Criteria 2020)

Uncertain significance
(Mar 5, 2021)

inherited

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000755856.6

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 452 of the ADSL protein (p.Arg452His). This variant is present in population databases (rs775671027, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ADSL-related conditions. ClinVar contains an entry for this variant (Variation ID: 529215). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 New York Genome Center - CSER-NYCKidSeq, SCV002099038.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

The inherited c.1355G>A (p.Arg452His) variant identified in the ADSL gene substitutes a well conserved Arginine for Histidine at amino acid 452/485 (exon 12/13). This variant is found with low frequency in gnomAD(v3.1) (6 heterozygotes, 0 homozygotes; allele frequency: 3.95e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score: 0.022) and Pathogenic (REVEL; score:0.822) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:529215), and to our current knowledge has not been reported in affected individuals in the literature although a different amino acid change at the same position has been reported in a pair of affected siblings [p.Arg452Pro; PMID:12368987]. The inherited c.1355G>A (p.Arg452His) variant identified in the ADSL gene is reported as a Variant of Uncertain Significance.

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

Last Updated: Sep 29, 2024

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