ClinVar Miner

Submissions for variant NM_000182.5(HADHA):c.274_278del (p.Ser92fs) (rs781205883)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169517 SCV000220987 likely pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2014-12-23 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185936 SCV000230047 pathogenic not provided 2014-06-30 criteria provided, single submitter clinical testing
GeneDx RCV000185936 SCV000238892 pathogenic not provided 2013-06-20 criteria provided, single submitter clinical testing The c.274_278delTCATC mutation in the HADHA gene has been reported previously in association with long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency using alternate nomenclature (Ibdah et al., 1999). The deletion causes a frameshift starting with codon Serine 92, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Ser92LysfsX10. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in HADHA panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000779319 SCV000915902 pathogenic HADHA-Related Disorders 2017-05-25 criteria provided, single submitter clinical testing The HADHA c.274_278delTCATC (p.Ser92LysfsTer10) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Ser92LysfsTer10 variant (also referred to as delta271-275 in the literature), has been reported in at least five studies and is found in a total of nine individuals with trifunctional protein (TFP) deficiency or LCHAD deficiency. Specifically, the p.Ser92LysfsTer10 variant was reported in a homozygous state in one infant with severe, neonatal-onset TFP deficiency (Boutron et al. 2011). It has also been reported in a compound heterozygous state in eight individuals with TFP or LCHAD deficiency with varying presentations (Ibdah et al. 1999; Yang et al. 2002; Gillingham et al. 2003; Boutron et al. 2011; Fletcher et al. 2012). Control data are unavailable for this variant which is also not reported in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Due to the potential impact of frameshift variants and the evidence from the literature, the p.Ser92LysfsTer10 variant is classified as pathogenic for HADHA-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001058997 SCV001223600 pathogenic Mitochondrial trifunctional protein deficiency; Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2019-01-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser92Lysfs*10) in the HADHA gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed as homozygous or in combination with another HDHA variant in several individuals affected with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency or mitochondrial trifunctional protein deficiency (PMID: 21549624, 27491397, 10352164, 12809642). ClinVar contains an entry for this variant (Variation ID: 189105). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169517 SCV001338656 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-04-23 criteria provided, single submitter clinical testing Variant summary: HADHA c.274_278delTCATC (p.Ser92LysfsX10) 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 8e-06 in 251432 control chromosomes (gnomAD). c.274_278delTCATC has been reported in a compound heterozygous state and a homozygous state in multiple individuals affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency or Mitochondrial Trifunctional Protein Deficiency (Ibdah_1999, Boutron_2011, Boese_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Undiagnosed Diseases Network,NIH RCV000169517 SCV001736870 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-04-30 criteria provided, single submitter clinical testing
Natera, Inc. RCV000169517 SCV001462521 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2020-09-16 no assertion criteria provided clinical testing

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