2-26212590-C-T

Position:

chr2-26212590-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000380649.8(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). Synonymous variant affecting the same amino acid position (i.e. G319G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

HADHA
ENST00000380649.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9

Conservation

PhyloP100: 7.07

Variant links:

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]

HADHA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HADHA	NM_000182.5 linkuse as main transcript	c.955G>A	p.Gly319Ser	missense_variant	10/20	ENST00000380649.8	NP_000173.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HADHA	ENST00000380649.8 linkuse as main transcript	c.955G>A	p.Gly319Ser	missense_variant	10/20	1	NM_000182.5	ENSP00000370023	P1	P40939-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251414

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000519

AC:

AN:

1444156

Hom.:

Cov.:

AF XY:

0.0000542

AC XY:

AN XY:

719750

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000675

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain: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. -

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

3.5

H;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.7

D;.;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0040

D;.;.

Sift4G

Uncertain

0.0060

D;.;.

Polyphen

1.0

D;.;.

Vest4

0.95

MutPred

0.79

Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);.;

MVP

0.94

MPC

0.80

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over