ClinVar Miner

Submissions for variant NM_000182.5(HADHA):c.180+3A>G (rs781222705)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185934 SCV000228808 pathogenic not provided 2014-10-13 criteria provided, single submitter clinical testing
GeneDx RCV000185934 SCV000238890 pathogenic not provided 2016-07-01 criteria provided, single submitter clinical testing The c.180+3 A>G splice site variant in the HADHA gene has been previously reported in association with mitochondrial trifunctional protein deficiency (Brackett et al., 1995). This variant reduces the quality of the splice donor site in intron 3, and is expected to cause abnormal gene splicing.
Fulgent Genetics,Fulgent Genetics RCV000763079 SCV000893602 pathogenic Mitochondrial trifunctional protein deficiency; Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000763079 SCV000945227 pathogenic Mitochondrial trifunctional protein deficiency; Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-09-13 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the HADHA gene. It does not directly change the encoded amino acid sequence of the HADHA protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs781222705, ExAC 0.02%). This variant has been observed in combination with another HADHA variant in individuals affected with mitochondrial trifunctional protein deficiency or long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (PMID: 7738175, 27491397, 23868323, 26109258) and in one of these individuals, the variant was observed on the opposite chromosome (in trans) from a likely pathogenic variant. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 8731). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change disrupts splicing (PMID: 7738175). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000984272 SCV001426898 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-07-02 criteria provided, single submitter clinical testing Variant summary: HADHA c.180+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site and one predicts the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions demonstrating the variant causes skipping of exon 3 resulting in premature stop codon (Brackett_1995). The variant allele was found at a frequency of 5.2e-05 in 251376 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HADHA causing Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (5.2e-05 vs 0.0019), allowing no conclusion about variant significance. c.180+3A>G has been reported in the literature in individuals affected with Mitochondrial Trifunctional Protein Deficiency and Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (e.g. Brackett_1995, Boese_2016, Djouadi_2016, Liewluck_2013). These data indicate that the variant is likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000009270 SCV000029488 pathogenic Mitochondrial trifunctional protein deficiency 1995-05-01 no assertion criteria provided literature only
Counsyl RCV000984272 SCV001132411 likely pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2015-09-11 no assertion criteria provided clinical testing
Natera, Inc. RCV000984272 SCV001462522 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-09-16 no assertion criteria provided clinical testing

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