ClinVar Miner

Submissions for variant NM_000182.4(HADHA):c.274_278delTCATC (p.Ser92Lysfs) (rs781205883)

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Total submissions: 5
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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 RCV000169517 SCV000230046 pathogenic Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2014-06-30 criteria provided, single submitter clinical testing
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.

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