Submissions for variant NM_018706.7(DHTKD1):c.2572+1G>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003088166	SCV003478785	likely pathogenic	2-aminoadipic 2-oxoadipic aciduria	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 15 of the DHTKD1 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 DHTKD1 are known to be pathogenic (PMID: 23141293, 25860818). This variant is present in population databases (rs776390640, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with DHTKD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2164699). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
PreventionGenetics, part of Exact Sciences	RCV003410082	SCV004110408	likely pathogenic	DHTKD1-related disorder	2023-09-18	criteria provided, single submitter	clinical testing	The DHTKD1 c.2572+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge this variant has not been reported in the literature. This variant is reported in 0.0045% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-12160918-G-A). Variants that disrupt the consensus splice donor site in DHTKD1 are expected to be pathogenic (see, for example, Hagen et al. 2015. PubMed ID: 25860818). This variant is interpreted as likely pathogenic.