Submissions for variant NM_000182.5(HADHA):c.1195C>T (p.Arg399Ter)

gnomAD frequency: 0.00001  dbSNP: rs1243779049

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523677	SCV000617631	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21549624, 33610471, 33638202, 33392894)
Counsyl	RCV000667154	SCV000791561	likely pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2017-05-12	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001169966	SCV001251679	pathogenic	Mitochondrial trifunctional protein deficiency	2020-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000667154	SCV001337807	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2020-01-13	criteria provided, single submitter	clinical testing	Variant summary: HADHA c.1195C>T (p.Arg399X) 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 was absent in 251486 control chromosomes. c.1195C>T has been reported in the literature in at-least one individual affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency who displayed MTP (Mitochondrial Trifunctional Protein) deficiency with a late infantile hepatic phenotype (Boutron_2011). These data support the notion that this variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported although haploinsufficiency has been reported as a major pathomechanism in MTP deficiency (Boutron_2011). 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 pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851488	SCV002224586	pathogenic	Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg399*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 21549624). ClinVar contains an entry for this variant (Variation ID: 449455). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000667154	SCV004191759	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2024-02-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000667154	SCV002076509	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2020-09-02	no assertion criteria provided	clinical testing