Submissions for variant NM_000182.5(HADHA):c.1637A>G (p.Tyr546Cys)

gnomAD frequency: 0.00007  dbSNP: rs370170143

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494150	SCV000582118	uncertain significance	not provided	2024-09-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Mayo Clinic Laboratories, Mayo Clinic	RCV000494150	SCV002541796	uncertain significance	not provided	2021-07-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527077	SCV003300620	uncertain significance	Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2022-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 546 of the HADHA protein (p.Tyr546Cys). This variant is present in population databases (rs370170143, gnomAD 0.02%). 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: 429528). 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230520	SCV003928835	uncertain significance	not specified	2023-04-04	criteria provided, single submitter	clinical testing	Variant summary: HADHA c.1637A>G (p.Tyr546Cys) results in a non-conservative amino acid change located in the 3-hydroxyacyl-CoA dehydrogenase, C-terminal (IPR006108) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251448 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in HADHA causing Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (4e-05 vs 0.0019), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1637A>G in individuals affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV000668659	SCV005060951	uncertain significance	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency		criteria provided, single submitter	clinical testing	The observed missense c.1637A>G (p.Tyr546Cys) variant in HADHA gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Tyr546Cys variant has been reported with allele frequency of 0.004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Uncertain Significance. The amino acid change p.Tyr546Cys in HADHA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Tyr at position 546 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).
Counsyl	RCV000668659	SCV000793293	uncertain significance	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	2019-06-17	no assertion criteria provided	clinical testing