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

dbSNP: rs747985669

Total submissions: 7

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).
Labcorp Genetics (formerly Invitae), Labcorp	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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000411664	SCV005086567	pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2024-09-22	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with LCHAD deficiency, (MIM#609016) and mitochondrial trifunctional protein (TFP) deficiency (MIM#609015). (I) 0106 - This gene is associated with autosomal recessive disease. There is currently no genotype-phenotype correlation distinguishing LCHAD and TFP deficiency; enzymatic assay will be required. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. (SP) 1207 - Parental origin of the variant is unresolved. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Counsyl	RCV000411664	SCV000486114	likely pathogenic	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2016-04-01	no assertion criteria provided	clinical testing