ClinVar Miner

Submissions for variant NM_004260.4(RECQL4):c.3393+2T>G

gnomAD frequency: 0.00003  dbSNP: rs557284122
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000819234 SCV000959882 likely pathogenic Baller-Gerold syndrome 2024-07-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 19 of the RECQL4 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 RECQL4 are known to be pathogenic (PMID: 12734318, 12952869). This variant is present in population databases (rs557284122, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with retinoblastoma (PMID: 31604778). ClinVar contains an entry for this variant (Variation ID: 661753). 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003444691 SCV004171461 likely pathogenic Rothmund-Thomson syndrome type 2 2023-10-16 criteria provided, single submitter clinical testing The RECQL4 c.3393+2T>G intronic change results in a T to G substitution at the +2 position of intron 19 of the RECQL4 gene and is predicted to disrupt the donor splice site resulting in loss of protein function and internal RNA data confirms out-of-frame exon skipping. To our knowledge, this variant has not been reported in individuals with RECQL4-associated disorders. It has been reported as heterozygous in individuals with retinoblastoma (PMID: 31604778, internal data). This variant has a maximum subpopulation frequency of 0.0083% in gnomAD v2.1.1. In summary, this variant meets criteria to be classified as likely pathogenic.
GeneDx RCV004777897 SCV005389078 uncertain significance not provided 2024-03-10 criteria provided, single submitter clinical testing Observed in the heterozygous state in an individual with retinoblastoma (PMID: 31604778); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 12734318, 12952869, 31604778)

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