VCV002138451.2 - ClinVar

NM_000026.4(ADSL):c.802G>C (p.Asp268His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000026.4(ADSL):c.802G>C (p.Asp268His)

Variation ID: 2138451 Accession: VCV002138451.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.1 22: 40361282 (GRCh38) [ NCBI UCSC ] 22: 40757286 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Feb 14, 2024	May 22, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000026.4:c.802G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000017.1:p.Asp268His	missense
NM_001123378.3:c.802G>C	NP_001116850.1:p.Asp268His	missense
NM_001317923.2:c.610G>C	NP_001304852.1:p.Asp204His	missense
NM_001363840.3:c.802G>C	NP_001350769.1:p.Asp268His	missense
NM_001410812.1:c.802G>C	NP_001397741.1:p.Asp268His	missense
NM_001410814.1:c.757G>C	NP_001397743.1:p.Asp253His	missense
NM_001410816.1:c.802G>C	NP_001397745.1:p.Asp268His	missense
NR_134256.2:n.861G>C		non-coding transcript variant
NC_000022.11:g.40361282G>C
NC_000022.10:g.40757286G>C
NG_007993.2:g.19783G>C

... more HGVS ... less HGVS

Protein change

D204H, D268H, D253H

Other names

Canonical SPDI

NC_000022.11:40361281:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ADSL		-	-	GRCh38 GRCh37	839	868

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Adenylosuccinate lyase deficiency	Pathogenic (1)	criteria provided, single submitter	May 22, 2022	RCV003064660.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 22, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Adenylosuccinate lyase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003444540.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 10888601‚ 20127976‚ 23055421‚ 29302074‚ 18524658 Comment: This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 268 of the ADSL protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 268 of the ADSL protein (p.Asp268His). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp268 amino acid residue in ADSL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10888601, 20127976, 23055421, 29302074). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ADSL function (PMID: 18524658). 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. This missense change has been observed in individual(s) with adenylosuccinate lyase deficiency (PMID: 18524658). (less)

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 268 of the ADSL protein (p.Asp268His). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp268 amino acid residue in ADSL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10888601, 20127976, 23055421, 29302074). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ADSL function (PMID: 18524658). 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. This missense change has been observed in individual(s) with adenylosuccinate lyase deficiency (PMID: 18524658).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetics of intellectual disability in consanguineous families.	Hu H	Molecular psychiatry	2019	PMID: 29302074
Novel proton MR spectroscopy findings in adenylosuccinate lyase deficiency.	Zulfiqar M	Journal of magnetic resonance imaging : JMRI	2013	PMID: 23055421
Biochemical and structural analysis of 14 mutant adsl enzyme complexes and correlation to phenotypic heterogeneity of adenylosuccinate lyase deficiency.	Zikanova M	Human mutation	2010	PMID: 20127976
Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency.	Jurecka A	Molecular genetics and metabolism	2008	PMID: 18524658
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	Human molecular genetics	2000	PMID: 10888601

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000026.4(ADSL):c.802G>C (p.Asp268His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...