Submissions for variant NM_000026.4(ADSL):c.153+1G>T

dbSNP: rs1555903969

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523755	SCV000618165	pathogenic	not provided	2016-07-26	criteria provided, single submitter	clinical testing	The c.153+1G>T pathogenic variant in the ADSL gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 1. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.153+1G>T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.153+1G>T as a pathogenic variant.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000610929	SCV000712875	uncertain significance	not specified	2017-04-28	criteria provided, single submitter	clinical testing	The c.153+1G>T (NM_000026.2 c.153+1G>T) variant in ADSL has not been reported in individuals with clinical features of adenylosuccinate lyase deficiency, and wa s absent from large population studies. This variant occurs in the invariant reg ion (+/- 1,2) of the splice donor consensus sequence of exon 1 and would be pred icted to cause altered splicing. However, exon 1 is not always transcribed and/ or translated such that the impact of this variant is less certain. In summary, additional data are required to determine the clinical significance of this var iant.
Invitae	RCV002525131	SCV003307725	likely pathogenic	Adenylosuccinate lyase deficiency	2022-02-20	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the ADSL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ADSL are known to be pathogenic (PMID: 10888601, 20177786). This variant has not been reported in the literature in individuals affected with ADSL-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 449773).