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 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. 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). ClinVar contains an entry for this variant (Variation ID: 431987). Disruption of this splice site has been observed in individual(s) with HADHB-related conditions (PMID: 24379101). This variant is present in population databases (rs776172237, gnomAD 0.008%). 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.

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