VCV000347133.15 - ClinVar

NM_005327.7(HADH):c.240G>A (p.Lys80=)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance (2); Likely benign (2)

4 out of 5 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005327.7(HADH):c.240G>A (p.Lys80=)

Variation ID: 347133 Accession: VCV000347133.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q25 4: 108009866 (GRCh38) [ NCBI UCSC ] 4: 108931022 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Feb 15, 2026	Sep 29, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_005327.7:c.240G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005318.6:p.Lys80=	synonymous
NM_001184705.2:c.240G>A
NM_001184705.4:c.240G>A	NP_001171634.3:p.Lys80=	synonymous
NM_001331027.2:c.252G>A	NP_001317956.2:p.Lys84=	synonymous
NC_000004.12:g.108009866G>A
NC_000004.11:g.108931022G>A
NG_008156.2:g.25083G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000004.12:108009865:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00006

The Genome Aggregation Database (gnomAD) 0.00007

The Genome Aggregation Database (gnomAD) 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00014

Links

ClinGen: CA3037391 dbSNP: rs748623569 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HADH		-	-	GRCh38 GRCh37	375	410

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hyperinsulinemic hypoglycemia, familial, 4	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000284074.5
Deficiency of 3-hydroxyacyl-CoA dehydrogenase	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Sep 29, 2025	RCV000339159.15
Hyperinsulinemic hypoglycemia	Likely benign (1)	criteria provided, single submitter	-	RCV003221353.1
HADH-related disorder	Likely benign (1)	no assertion criteria provided	Oct 12, 2020	RCV003897785.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Hyperinsulinemic hypoglycemia, familial, 4	Illumina Laboratory Services, Illumina Accession: SCV000446836.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Deficiency of 3-hydroxyacyl-CoA dehydrogenase	Illumina Laboratory Services, Illumina Accession: SCV000446837.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (-) C Contributing to aggregate classification	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)	Hyperinsulinemic hypoglycemia (Autosomal recessive inheritance)	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV003915692.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (3) PubMed: 29280746‚ 34055426‚ 34547194 Comment: show 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 rs748623569 in congenital hyperinsulinism is yet to be ascertained. (less) Observation: 1 Collection method: research Allele origin: unknown Affected status: unknown Observation 1 Collection method: research Allele origin: unknown Affected status: unknown

Likely benign (Sep 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Deficiency of 3-hydroxyacyl-CoA dehydrogenase	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002397521.5 First in ClinVar: Apr 11, 2022 Last updated: Feb 15, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Oct 12, 2020) N Not contributing to aggregate classification	no assertion criteria provided	HADH-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004712844.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

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 rs748623569 in congenital hyperinsulinism is yet to be ascertained.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Congenital hyperinsulinism: recent updates on molecular mechanisms, diagnosis and management.	Giri D	Journal of pediatric endocrinology & metabolism : JPEM	2021	PMID: 34547194
Genotyping of ABCC8, KCNJ11, and HADH in Iranian Infants with Congenital Hyperinsulinism.	Hashemian S	Case reports in endocrinology	2021	PMID: 34055426
Congenital Hyperinsulinism: Diagnosis and Treatment Update.	Demirbilek H	Journal of clinical research in pediatric endocrinology	2017	PMID: 29280746

Text-mined citations for rs748623569 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026