rs752317877
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000182.5(HADHA):c.955G>A(p.Gly319Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000495 in 1,596,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000052 ( 0 hom. )
Consequence
HADHA
NM_000182.5 missense
NM_000182.5 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 7.07
Genes affected
HADHA (HGNC:4801): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha) This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. Mutations in this gene result in trifunctional protein deficiency or LCHAD deficiency. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.933
PP5
Variant 2-26212590-C-T is Pathogenic according to our data. Variant chr2-26212590-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203743.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=1, Likely_pathogenic=1}. Variant chr2-26212590-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152084Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251414Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135866
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GnomAD4 exome AF: 0.0000519 AC: 75AN: 1444156Hom.: 0 Cov.: 26 AF XY: 0.0000542 AC XY: 39AN XY: 719750
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74272
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 29, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 10, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 16, 2017 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | HADHA: PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 2016 | A variant of uncertain significance has also been identified in the HADHA gene. The G319S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G319S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G319S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;CN376812:Mitochondrial trifunctional protein deficiency 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 06, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 10, 2024 | Variant summary: HADHA c.955G>A (p.Gly319Ser) results in a non-conservative amino acid change in 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 1.6e-05 in 251414 control chromosomes. c.955G>A has been reported in the literature in at least two compound heterozygous individuals affected with HADHA-related conditions (e.g., Diebold_2019, Grunert_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30682426, 33638202). ClinVar contains an entry for this variant (Variation ID: 203743). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2017 | - - |
HADHA-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 07, 2024 | The HADHA c.955G>A variant is predicted to result in the amino acid substitution p.Gly319Ser. This variant was reported in the compound heterozygous state in an individual with neuropathy, distal muscle atrophy, exercise intolerance. The patient had a normal newborn screening and had repeatedly normal blood acylcarnitine levels (Patient 2; Table A1, A2, Diebold et al. 2019. PubMed ID: 30682426). The variant was also reported in the homozygous state in 2 individuals with features of Charcot Marie Tooth disease from consanguineous parents. Both patients also had normal acylcarnitine profiles (Khani et al. 2020. PubMed ID: 32897397). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. It is interpreted as uncertain by most submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/203743/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Mitochondrial trifunctional protein deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Children's Medical Center, Molecular Pathology and Cytogenetics Lab, Tehran University of Medical Sciences | - | For this missense variant, computational prediction tools unanimously support a deleterious effect on the gene and the frequency of this variant is extremely low in gnomAD population databases. - |
Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 08, 2021 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 319 of the HADHA protein (p.Gly319Ser). This variant is present in population databases (rs752317877, gnomAD 0.006%). This missense change has been observed in individual(s) with peripheral neuropathy (PMID: 30682426). ClinVar contains an entry for this variant (Variation ID: 203743). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.
Sift4G
Uncertain
D;.;.
Polyphen
D;.;.
Vest4
MutPred
Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at