ClinVar Miner

Submissions for variant NM_000191.3(HMGCL):c.497+4A>G (rs568718845)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665452 SCV000789581 uncertain significance Deficiency of hydroxymethylglutaryl-CoA lyase 2017-02-14 criteria provided, single submitter clinical testing
GeneDx RCV000498294 SCV000589487 likely pathogenic not provided 2015-10-05 criteria provided, single submitter clinical testing An individual with symptoms associated with HMG-CoA lyase deficiency was heterozygous for this variant and a nonsense variant; however, parental testing was not done to confirm the variants were in trans (Menao et al., 2009). Functional analysis found that the c.497+4 A>G variant results in alternative splicing with 2 transcripts, one bearing a five-exon deletion and the other with deletion of exons 5 and 6 (Menao et al., 2009). Additionally, this nucleotide substitution occurs at a position that is conserved across species and several in-silico splice prediction models predict that c.497+4 A>G creates a cryptic donor site in intron 5. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

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