rs76476980

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP4_StrongBS1_SupportingBS2

The NM_005327.7(HADH):c.662G>A(p.Arg221His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000621 in 1,609,822 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R221C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 2 hom. )

Consequence

HADH
NM_005327.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:5

Conservation

PhyloP100: 8.15

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

3-hydroxyacyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, ClinGen
hyperinsulinemic hypoglycemia, familial, 4
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

HADH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.017106831).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00331 (504/152126) while in subpopulation AFR AF = 0.0114 (474/41498). AF 95% confidence interval is 0.0106. There are 3 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HADH	NM_005327.7 link	c.662G>A	p.Arg221His	missense_variant	Exon 6 of 8	ENST00000309522.8	NP_005318.6	Q16836-1A0A140VK76
HADH	NM_001184705.4 link	c.662G>A	p.Arg221His	missense_variant	Exon 6 of 9		NP_001171634.3	Q16836-3
HADH	NM_001331027.2 link	c.674G>A	p.Arg225His	missense_variant	Exon 6 of 8		NP_001317956.2	B3KTT6
HADH	XR_007096395.1 link	n.706G>A		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.662G>A	p.Arg221His	missense_variant	Exon 6 of 8	1	NM_005327.7	ENSP00000312288.4		Q16836-1

Frequencies

GnomAD3 genomes

AF:

0.00331

AC:

503

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000871

AC:

219

AN:

251434

AF XY:

0.000596

show subpopulations

Gnomad AFR exome

AF:

0.0121

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000340

AC:

496

AN:

1457696

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

235

AN XY:

725508

show subpopulations

African (AFR)

AF:

0.0113

AC:

377

AN:

33396

American (AMR)

AF:

0.000604

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000869

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000325

AC:

AN:

1108198

Other (OTH)

AF:

0.000697

AC:

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00331

AC:

504

AN:

152126

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

223

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0114

AC:

474

AN:

41498

American (AMR)

AF:

0.00131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

67988

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00166

Hom.:

Bravo

AF:

0.00393

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00105

AC:

128

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 4

Pathogenic:1Benign:1

Feb 10, 2024

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Potent mutations in HADH gene are associated with congenital hyperinsulinism, which leads to recurrent hypoglycemia. The condition is exacerbated by stress, fasting or excessive dietary protein. May respond well to diazoxide. However, the role of this particular variant rs76476980 in hyperinsulinemic hypoglycemia is yet to be ascertained. This variant is a potent moderate impact, deleterious variant with a CADD score of 31. This gene is found to be frequently associated with Hyperinsulinemic hypoglycemia as per recent evidence as well, with sufficient scientific evidence to support the reported classification. Loss of function mutations in HADH can potentially cause protein-induced hyperinsulinemic hypoglycemia -

Jun 26, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided

Uncertain:1Benign:1

Apr 01, 2015

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R221H variant in the HADH gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Sequencing Project reports R221H was observed in 42/4406 alleles (0.95%) from individuals of African American background, indicating it may be a rare variant in this population. The R221H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense pathogenic variant in a nearby residues (Y226H) has been reported in the Human Gene Mutation Database in association with hyperinsulinemic hypoglycemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R221H as a variant of unknown significance. -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HADH: BS1, BS2 -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 26, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Deficiency of 3-hydroxyacyl-CoA dehydrogenase;C1864948:Hyperinsulinemic hypoglycemia, familial, 4

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Uncertain:1

Jan 12, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

ACMG criteria: PP3 (10 predictors), BS2 (27 cases and 24 controls in type2diabetesgenetics.org)=VUS NOTE: GeneDx also calls VUS -

not specified

Benign:1

Mar 07, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

.;.;D;.;T;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

MetaRNN

Benign

0.017

T;T;T;T;T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

3.6

.;H;H;.;.;.

PhyloP100

8.1

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.9

.;.;D;.;D;.

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

.;.;D;.;D;.

Sift4G

Pathogenic

0.0010

.;D;D;.;.;D

Polyphen

1.0

.;.;D;.;.;.

Vest4

0.72, 0.71, 0.71

MVP

0.99

MPC

0.97

ClinPred

0.15

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.92

gMVP

0.92

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over