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

dbSNP: rs781205883

Total submissions: 10

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
Eurofins Ntd Llc (ga)	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 Laboratory Services, Illumina	RCV000779319	SCV000915902	pathogenic	HADHA-related disorder	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058997	SCV001223600	pathogenic	Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2024-07-04	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. Loss-of-function variants in HADHA are known to be pathogenic (PMID: 7738175, 21103935, 21549624, 22459206). This variant is present in population databases (rs781205883, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency or mitochondrial trifunctional protein deficiency (PMID: 10352164, 12809642, 21549624, 27491397). ClinVar contains an entry for this variant (Variation ID: 189105). 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
Baylor Genetics	RCV000169517	SCV004191755	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2023-12-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000185936	SCV005042418	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	HADHA: PVS1, PM2, PM3
Natera, Inc.	RCV000169517	SCV001462521	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing