chr7-66086797-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000048.4(ASL):c.578G>A(p.Arg193Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000699 in 1,587,274 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. R193W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000048.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.578G>A | p.Arg193Gln | missense_variant | 8/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.578G>A | p.Arg193Gln | missense_variant | 7/16 | ||
ASL | NM_001024944.2 | c.578G>A | p.Arg193Gln | missense_variant | 7/15 | ||
ASL | NM_001024946.2 | c.524+135G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.578G>A | p.Arg193Gln | missense_variant | 8/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152146Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000198 AC: 4AN: 201534Hom.: 0 AF XY: 0.0000276 AC XY: 3AN XY: 108802
GnomAD4 exome AF: 0.0000732 AC: 105AN: 1435128Hom.: 0 Cov.: 32 AF XY: 0.0000745 AC XY: 53AN XY: 711744
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74326
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 15, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 22, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2023 | Variant summary: ASL c.578G>A (p.Arg193Gln) results in a conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 201534 control chromosomes. c.578G>A has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria, and was reported confirmed in trans in at least one patient (example Balmer_2014, Kleijer_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant impacting the same amino acid has been reported in HGMD in association with Argininosuccinate lyase deficiency and has been classified as pathogenic by at least one lab in ClinVar (p.R193W). Six ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=4) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2017 | The p.Arg193Gln (NM_000048.3 c.578G>A) variant in ASL has been reported in 7 com pound heterozygous individuals and 1 homozygous individual with clinical feature s of argininosuccinate lyase deficiency (Barbosa 1991, Kleijer 2002, Linnebank 2 002, and Balmer 2014). This variant has also been identified in 2/22,098 of Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs373697663). In vitro functional studies provide some evidenc e that this variant may impact protein function (Hu 2014); however these types o f assays may not accurately represent biological function. This variant has also been reported in ClinVar (Variation ID#372306). In summary, although additiona l studies are required to fully establish its clinical significance, the p.Arg19 3Gln variant is likely pathogenic for ASL in an autosomal recessive manner based on biallelic observations in patients, impact in functional studies, and low po pulation frequency. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 193 of the ASL protein (p.Arg193Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 705937, 12408190, 24166829). ClinVar contains an entry for this variant (Variation ID: 372306). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ASL function (PMID: 25778938). This variant disrupts the p.Arg193 amino acid residue in ASL. Other variant(s) that disrupt this residue have been observed in individuals with ASL-related conditions (PMID: 24166829), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 11, 2016 | The R193Q missense variant has reported previously in association with argininosuccinic aciduria (Barbosa et al. 1991; Linnebank et al. 2002). The R193Q variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R193Q variant is a semi-conservative amino acid substitution, it occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at the same residue (R193W) has also been reported in the Human Gene Mutation Database in association with argininosuccinic aciduria (Stenson et al., 2014), supporting the functional importance of this region of the protein. I summary, we interpret R193Q to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at