ClinVar Miner

Submissions for variant NM_000182.5(HADHA):c.1811del (p.Gly604fs)

dbSNP: rs747985669
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413009 SCV000491629 pathogenic not provided 2018-09-14 criteria provided, single submitter clinical testing The c.1811delG variant in the HADHA gene causes a frameshift starting with codon Glycine 604, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 16 of the new reading frame, denoted p.Gly604AlafsX16. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1811delG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000411664 SCV001339048 likely pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-03-12 criteria provided, single submitter clinical testing Variant summary: HADHA c.1811delG (p.Gly604AlafsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes. To our knowledge, no occurrence of c.1811delG in individuals affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology RCV002272218 SCV002556918 pathogenic Mitochondrial trifunctional protein deficiency 2021-03-04 criteria provided, single submitter clinical testing The HADHA c.1811delG variant is classified as Pathogenic (PVS1, PM2, PP5) The HADHA c.1811del variant is a single nucleotide deletion in exon 11 of 20 which is predicted to create a frameshift at position 604 in the protein, causing a premature termination codon 16 amino acids downstream (PVS1). The variant is in dbSNP (rs747985669) and is present at a low frequency in population databases (gnomAD 1 het/251482, 0 homozygotes) (PM2). The variant has been reported in the ClinVar database as pathogenic by another diagnostic laboratory (Variation ID 370726) (PP5).
Invitae RCV002523857 SCV003005620 pathogenic Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2023-03-18 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370726). This variant has not been reported in the literature in individuals affected with HADHA-related conditions. This variant is present in population databases (rs747985669, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gly604Alafs*16) in the HADHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HADHA are known to be pathogenic (PMID: 7738175, 21103935, 21549624, 22459206).
Baylor Genetics RCV000411664 SCV004191780 likely pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2023-04-22 criteria provided, single submitter clinical testing
Counsyl RCV000411664 SCV000486114 likely pathogenic Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2016-04-01 no assertion criteria provided clinical testing

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