rs146036912

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_005327.7(HADH):c.676T>C(p.Tyr226His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,611,286 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

HADH
NM_005327.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 8.02

Variant links:

Genes affected

HADH (HGNC:4799): (hydroxyacyl-CoA dehydrogenase) This gene is a member of the 3-hydroxyacyl-CoA dehydrogenase gene family. The encoded protein functions in the mitochondrial matrix to catalyze the oxidation of straight-chain 3-hydroxyacyl-CoAs as part of the beta-oxidation pathway. Its enzymatic activity is highest with medium-chain-length fatty acids. Mutations in this gene cause one form of familial hyperinsulinemic hypoglycemia. The human genome contains a related pseudogene of this gene on chromosome 15. [provided by RefSeq, May 2010]

HADH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

PP5

Variant 4-108027727-T-C is Pathogenic according to our data. Variant chr4-108027727-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212734.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADH	NM_005327.7 link	c.676T>C	p.Tyr226His	missense_variant	Exon 6 of 8	ENST00000309522.8	NP_005318.6	Q16836-1A0A140VK76
HADH	NM_001184705.4 link	c.676T>C	p.Tyr226His	missense_variant	Exon 6 of 9		NP_001171634.3	Q16836-3
HADH	NM_001331027.2 link	c.688T>C	p.Tyr230His	missense_variant	Exon 6 of 8		NP_001317956.2	B3KTT6
HADH	XR_007096395.1 link	n.720T>C		non_coding_transcript_exon_variant	Exon 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8 link	c.676T>C	p.Tyr226His	missense_variant	Exon 6 of 8	1	NM_005327.7	ENSP00000312288.4		Q16836-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000676

AC:

AN:

251452

AF XY:

0.0000662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000195

AC:

284

AN:

1459152

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

148

AN XY:

726118

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

AC:

AN:

33420

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44722

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26114

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39696

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86186

Gnomad4 FIN exome

AF:

0.0000375

AC:

AN:

53404

Gnomad4 NFE exome

AF:

0.000245

AC:

272

AN:

1109534

Gnomad4 Remaining exome

AF:

0.000149

AC:

AN:

60316

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000724

AC:

0.0000723903

AN:

0.0000723903

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000191

AC:

0.000191165

AN:

0.000191165

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of 3-hydroxyacyl-CoA dehydrogenase

Pathogenic:2Uncertain:1

Nov 19, 2014

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 226 of the HADH protein (p.Tyr226His). This variant is present in population databases (rs146036912, gnomAD 0.02%). This missense change has been observed in individual(s) with M/SCHAD deficiency (PMID: 16725361). This variant is also known as p.Y214H. ClinVar contains an entry for this variant (Variation ID: 212734). 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"). Experimental studies have shown that this missense change affects HADH function (PMID: 16725361). 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. -

Familial hyperinsulinism

Pathogenic:1

Mar 18, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HADH c.676T>C (p.Tyr226His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251452 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HADH causing Familial Hyperinsulinism (6.8e-05 vs 0.0005), allowing no conclusion about variant significance. c.676T>C (aka Y214H) has been reported in the literature in individuals with atypical clinical phenotypes, potentially overlapping with HADH-related disorders (e.g., Bennett_2006, Doan_2019), and in one of these cases, HADH activity was reduced to ~50% of the control value in patient derived fibroblasts (Bennett_2006). Authors of this study also reported experimental evidence evaluating an impact on protein function and demonstrated that the Y214H variant protein had no detectable activity in an in vitro expression system (Bennett_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16725361, 31209396). ClinVar contains an entry for this variant (Variation ID: 212734). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hyperinsulinemic hypoglycemia, familial, 4

Uncertain:1

Nov 02, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Tyr226His variant in HADH has been reported in 1 individual with hepatic disease (PMID: 16725361) and has been identified in in 0.02% (21/129162) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs146036912). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 212734) and has been interpreted as likely pathogenic by Knight Diagnostic Laboratories (Oregon Health and Sciences University) and as a VUS by Invitae. In vitro functional studies provide some evidence that the p.Tyr226His variant may slightly impact protein function (PMID: 16725361). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Tyr226His variant is uncertain. ACMG/AMP Criteria applied: PS3_supporting, PP3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

.;.;D;.;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

.;M;M;.;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.1

.;.;D;.;D;.

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0050

.;.;D;.;D;.

Sift4G

Uncertain

0.022

.;D;D;.;.;D

Polyphen

1.0

.;.;D;.;.;.

Vest4

0.78, 0.81, 0.81

MVP

0.97

MPC

1.0

ClinPred

0.92

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.89

Mutation Taster

=3/97

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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