HADH p.Arg236*

Variant names:

• chr4-108027745-AG-TA
• NM_005327.7:c.694_695delAGinsTA
• HADH p.Arg232*

Your query was ambiguous. Multiple possible variants found:

• chr4-108027745-AG-TA
• chr4-108027757-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_005327.7(HADH):​c.694_695delAGinsTA​(p.Arg232*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R232R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HADH NM_005327.7 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.15
• Publications: 0 publications found

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, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hyperinsulinemic hypoglycemia, familial, 4

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005327.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	NM_005327.7	MANE Select	c.694_695delAGinsTA	p.Arg232*	stop_gained	N/A	NP_005318.6	Q16836-1
	HADH	NM_001184705.4		c.694_695delAGinsTA	p.Arg232*	stop_gained	N/A	NP_001171634.3
	HADH	NM_001331027.2		c.706_707delAGinsTA	p.Arg236*	stop_gained	N/A	NP_001317956.2	A0A0D9SFP2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADH	ENST00000309522.8	TSL:1 MANE Select	c.694_695delAGinsTA	p.Arg232*	stop_gained	N/A	ENSP00000312288.4	Q16836-1
	HADH	ENST00000505878.4	TSL:1	c.871_872delAGinsTA	p.Arg291*	stop_gained	N/A	ENSP00000425952.2	E9PF18
	HADH	ENST00000603302.5	TSL:1	c.694_695delAGinsTA	p.Arg232*	stop_gained	N/A	ENSP00000474560.1	Q16836-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-108948901;