ClinVar Miner

Submissions for variant NM_015214.3(DDHD2):c.1126-2A>G

dbSNP: rs2130822605
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002266477 SCV002548524 likely pathogenic Hereditary spastic paraplegia 54 2022-05-16 criteria provided, single submitter clinical testing Variant summary: DDHD2 c.1126-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 186800 control chromosomes. To our knowledge, no occurrence of c.1126-2A>G in individuals affected with Hereditary Spastic Paraplegia 54 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV002266477 SCV003342047 likely pathogenic Hereditary spastic paraplegia 54 2023-07-17 criteria provided, single submitter clinical testing 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: 1696332). This variant has not been reported in the literature in individuals affected with DDHD2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the DDHD2 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 DDHD2 are known to be pathogenic (PMID: 23176823, 23486545).

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