7-66087369-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000048.4(ASL):c.638G>A(p.Arg213Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,606,744 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000048.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.638G>A | p.Arg213Gln | missense_variant | 9/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.638G>A | p.Arg213Gln | missense_variant | 8/16 | ||
ASL | NM_001024944.2 | c.638G>A | p.Arg213Gln | missense_variant | 8/15 | ||
ASL | NM_001024946.2 | c.560G>A | p.Arg187Gln | missense_variant | 7/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.638G>A | p.Arg213Gln | missense_variant | 9/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 151900Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1454844Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2AN XY: 724072
GnomAD4 genome AF: 0.0000197 AC: 3AN: 151900Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74186
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 16, 2022 | - - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Jun 04, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 23, 2023 | Variant summary: ASL c.638G>A (p.Arg213Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the Fumarate lyase, N-terminal (IPR022761) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245196 control chromosomes (gnomAD). c.638G>A has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria (Ali_2019, Balmer_2014), and one was reported as compound heterozygous with another pathogenic variant. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31709144, 24166829). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 18, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 213 of the ASL protein (p.Arg213Gln). For these reasons, this variant has been classified as Pathogenic. 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 ASL protein function. ClinVar contains an entry for this variant (Variation ID: 558682). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 24166829, 31709144; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.01%). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24166829, 31709144) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at