ClinVar Miner

Submissions for variant NM_000183.3(HADHB):c.254+1G>A

gnomAD frequency: 0.00001  dbSNP: rs776172237
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498035 SCV000589624 pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing The c.254+1 G>A variant has been reported in a patient with mitochondrial trifunctional protein deficiency who harbored a missense variant on the opposite HADHB allele (in trans) (Terrone et al. 2014). The c.254+1 G>A variant destroys the canonical splice donor site in intron 5. Sequencing of the reported patient's mRNA revealed both a wild-type transcript and a transcript lacking exon 5 consistent with c.254+1 G>A causing abnormal gene splicing (Terrone et al. 2014). The c.254+1 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we interpret this variant as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000763080 SCV000893603 pathogenic Mitochondrial trifunctional protein deficiency 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV004568626 SCV004191812 pathogenic Mitochondrial trifunctional protein deficiency 1 2024-03-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000763080 SCV004292065 likely pathogenic Mitochondrial trifunctional protein deficiency 2023-05-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the HADHB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs776172237, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with HADHB-related conditions (PMID: 24379101). ClinVar contains an entry for this variant (Variation ID: 431987). Studies have shown that disruption of this splice site results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 24379101). 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.

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