ClinVar Miner

Submissions for variant NM_000026.4(ADSL):c.71C>T (p.Pro24Leu)

gnomAD frequency: 0.00001  dbSNP: rs1257907226
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000634534 SCV000755852 pathogenic Adenylosuccinate lyase deficiency 2022-11-08 criteria provided, single submitter clinical testing 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: 529212). This missense change has been observed in individual(s) with clinical features of adenylosuccinate lyase deficiency (PMID: 28487569, 30185235). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. 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 sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 24 of the ADSL protein (p.Pro24Leu).
Ambry Genetics RCV002529825 SCV003598742 uncertain significance Inborn genetic diseases 2021-12-21 criteria provided, single submitter clinical testing The c.71C>T (p.P24L) alteration is located in exon 1 (coding exon 1) of the ADSL gene. This alteration results from a C to T substitution at nucleotide position 71, causing the proline (P) at amino acid position 24 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
3billion RCV000634534 SCV004013665 likely pathogenic Adenylosuccinate lyase deficiency criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.77). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ADSL related disorder (ClinVar ID: VCV000529212 / PMID: 28487569). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 10958654). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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