2-26214447-A-T

Variant names:

• chr2-26214447-A-T
• rs137852774
• NM_000182.5:c.914T>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000182.5(HADHA):​c.914T>A​(p.Ile305Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,295,830 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I305T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: HADHA NM_000182.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.46
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• mitochondrial trifunctional protein deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-26214447-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 453019.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 2-26214447-A-T is Pathogenic according to our data. Variant chr2-26214447-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADHA	NM_000182.5	c.914T>A	p.Ile305Asn	missense_variant	Exon 9 of 20	ENST00000380649.8	NP_000173.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADHA	ENST00000380649.8	c.914T>A	p.Ile305Asn	missense_variant	Exon 9 of 20	1	NM_000182.5	ENSP00000370023.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251006 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000262 AC: 34 AN: 1295830 Hom.: 0 Cov.: 20 AF XY: 0.0000337 AC XY: 22 AN XY: 653692

African (AFR) AF: 0.00 AC: 0 AN: 30300

American (AMR) AF: 0.00 AC: 0 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25120

East Asian (EAS) AF: 0.00 AC: 0 AN: 38934

South Asian (SAS) AF: 0.00 AC: 0 AN: 82758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3858

European-Non Finnish (NFE) AF: 0.0000343 AC: 33 AN: 962332

Other (OTH) AF: 0.0000183 AC: 1 AN: 54656

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;CN376812:Mitochondrial trifunctional protein deficiency 1 Pathogenic:2

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:2

Mar 17, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mitochondrial trifunctional protein deficiency 1 Pathogenic:1

Sep 15, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 01, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9739053, 2019931, 21549624, 26109258, 29268767, 33610471, 32253025, 31589614) -

Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1

Jan 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 305 of the HADHA protein (p.Ile305Asn). This variant is present in population databases (rs137852774, gnomAD 0.002%). This missense change has been observed in individual(s) with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and/or MTP deficiency (PMID: 9739053, 21549624, 26109258, 29268767). ClinVar contains an entry for this variant (Variation ID: 8736). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	4.3	H;.;.
PhyloP100		8.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.6	D;.;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;.;.
Sift4G	Pathogenic	0.0010	D;.;.
Polyphen		0.99	D;.;.
Vest4		0.99
MutPred		0.89		Loss of stability (P = 0.0038);Loss of stability (P = 0.0038);.;
MVP		0.92
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.91
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852774; hg19: chr2-26437316;