Submissions for variant NM_000182.5(HADHA):c.16G>C (p.Ala6Pro)

dbSNP: rs150565988

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000324084	SCV000429539	uncertain significance	Mitochondrial trifunctional protein deficiency	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001141193	SCV000429540	uncertain significance	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001141193	SCV001301520	uncertain significance	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507551	SCV001713159	uncertain significance	not provided	2020-07-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001507551	SCV001810772	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519960	SCV002972043	uncertain significance	Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2022-04-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 6 of the HADHA protein (p.Ala6Pro). This variant is present in population databases (rs150565988, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with HADHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 335390). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HADHA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001507551	SCV005331428	uncertain significance	not provided	2024-08-01	criteria provided, single submitter	clinical testing	HADHA: PM2
Natera, Inc.	RCV001141193	SCV002076533	uncertain significance	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2019-10-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004735487	SCV005350267	uncertain significance	HADHA-related disorder	2024-08-13	no assertion criteria provided	clinical testing	The HADHA c.16G>C variant is predicted to result in the amino acid substitution p.Ala6Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.