NM_000026.4(ADSL):c.502G>A (p.Val168Ile) AND Adenylosuccinate lyase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 12, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV001330907.5

Allele description [Variation Report for NM_000026.4(ADSL):c.502G>A (p.Val168Ile)]

NM_000026.4(ADSL):c.502G>A (p.Val168Ile)

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.502G>A (p.Val168Ile)

HGVS:

NC_000022.11:g.40358883G>A
NG_007993.2:g.17384G>A
NM_000026.4:c.502G>AMANE SELECT
NM_001123378.3:c.502G>A
NM_001317923.2:c.310G>A
NM_001363840.3:c.502G>A
NP_000017.1:p.Val168Ile
NP_001116850.1:p.Val168Ile
NP_001304852.1:p.Val104Ile
NP_001350769.1:p.Val168Ile
NC_000022.10:g.40754887G>A
NM_000026.2:c.502G>A
NM_000026.3:c.502G>A
NR_134256.2:n.561G>A
p.Val168Ile

Protein change:

V104I

Links:

dbSNP: rs1385675650

NCBI 1000 Genomes Browser:

rs1385675650

Molecular consequence:

NM_000026.4:c.502G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001123378.3:c.502G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001317923.2:c.310G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363840.3:c.502G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_134256.2:n.561G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV001522760	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 2, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003322781	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 12, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33648541, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001522760

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 2, 2020)

unknown

clinical testing

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

SCV003322781

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 12, 2022)

germline

clinical testing

PubMed (2)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Clinical and molecular characterization of patients with adenylosuccinate lyase deficiency.

Mastrogiorgio G, Macchiaiolo M, Buonuomo PS, Bellacchio E, Bordi M, Vecchio D, Brown KP, Watson NK, Contardi B, Cecconi F, Tartaglia M, Bartuli A.

Orphanet J Rare Dis. 2021 Mar 1;16(1):112. doi: 10.1186/s13023-021-01731-6.

PubMed [citation]

PMID:: 33648541
PMCID:: PMC7919308

See all PubMed Citations (3)

Details of each submission

From Baylor Genetics, SCV001522760.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003322781.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 168 of the ADSL protein (p.Val168Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adenylosuccinate lyase deficiency (PMID: 33648541). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1029580). 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. For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: Sep 29, 2024

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