rs771121666
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_000026.4(ADSL):c.1342T>C(p.Ser448Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S448C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000026.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADSL | NM_000026.4 | c.1342T>C | p.Ser448Pro | missense_variant | 12/13 | ENST00000623063.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADSL | ENST00000623063.3 | c.1342T>C | p.Ser448Pro | missense_variant | 12/13 | 1 | NM_000026.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251482Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135918
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461812Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727210
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Adenylosuccinate lyase deficiency Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 12, 2018 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in two unrelated patients with ADSL deficiency in compound heterozygous with other variants [PMID 16839792, 24781210] - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 11, 2023 | Variant summary: ADSL c.1342T>C (p.Ser448Pro) results in a non-conservative amino acid change located in the Adenylosuccinate lyase C-terminal (IPR019468) 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 251482 control chromosomes (gnomAD). c.1342T>C has been reported in the literature in individuals affected with Adenylosuccinate Lyase Deficiency (Spiegel_2006, Michael_2014), and one was compound heterozygous with a variant that has been classified as pathogenic by a ClinVar submitter. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16839792, 24781210). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=2), likely pathogenic (n=2), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | This variant is present in population databases (rs771121666, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 448 of the ADSL protein (p.Ser448Pro). This missense change has been observed in individual(s) with clinical features of ADSL-related conditions ‚Äã (PMID: 16839792, 24781210; Invitae). 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 not expected to disrupt ADSL protein function. ClinVar contains an entry for this variant (Variation ID: 235410). - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2023 | Biochemical testing in one of the previously reported individuals revealed elevated succinyladenosine urinary excretion, confirming dysfunction of adenylosuccinate lyase (ADSL) (Michaud et al., 2014); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16839792, 24781210) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 05, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2022 | The c.1342T>C (p.S448P) alteration is located in exon 12 (coding exon 12) of the ADSL gene. This alteration results from a T to C substitution at nucleotide position 1342, causing the serine (S) at amino acid position 448 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at