ClinVar Miner

Submissions for variant NM_000182.5(HADHA):c.180+1G>A (rs786205088)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665265 SCV000789356 likely pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2017-02-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000009269 SCV001361811 likely pathogenic Mitochondrial trifunctional protein deficiency 2019-06-14 criteria provided, single submitter clinical testing Variant summary: HADHA c.180+1G>A 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 a 5' splicing donor site. Two predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251376 control chromosomes (gnomAD). c.180+1G>A has been reported in the literature in at least one individual affected with Mitochondrial trifunctional protein deficiency with deletion of exon 3 of HADHA cDNA (Brackett_1995, Ibdah_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001382535 SCV001581366 pathogenic Mitochondrial trifunctional protein deficiency; Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-07-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the HADHA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 7738175). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 8730). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 7738175). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HADHA are known to be pathogenic (PMID: 7738175, 21103935, 21549624, 22459206). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009269 SCV000029487 pathogenic Mitochondrial trifunctional protein deficiency 1995-05-01 no assertion criteria provided literature only

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