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NM_005327.7(HADH):c.676T>C (p.Tyr226His) AND Hyperinsulinemic hypoglycemia, familial, 4

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Nov 2, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001762415.3

Allele description [Variation Report for NM_005327.7(HADH):c.676T>C (p.Tyr226His)]

NM_005327.7(HADH):c.676T>C (p.Tyr226His)

Gene:
HADH:hydroxyacyl-CoA dehydrogenase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4q25
Genomic location:
Preferred name:
NM_005327.7(HADH):c.676T>C (p.Tyr226His)
Other names:
NM_005327.5(HADH):c.676T>C
HGVS:
  • NC_000004.12:g.108027727T>C
  • NG_008156.2:g.42944T>C
  • NM_001184705.4:c.676T>C
  • NM_001331027.2:c.688T>C
  • NM_005327.7:c.676T>CMANE SELECT
  • NP_001171634.2:p.Tyr226His
  • NP_001171634.3:p.Tyr226His
  • NP_001317956.2:p.Tyr230His
  • NP_005318.6:p.Tyr226His
  • NC_000004.11:g.108948883T>C
  • NC_000004.11:g.108948883T>C
  • NM_001184705.2:c.676T>C
  • NM_005327.4:c.676T>C
Protein change:
Y226H
Links:
dbSNP: rs146036912
NCBI 1000 Genomes Browser:
rs146036912
Molecular consequence:
  • NM_001184705.4:c.676T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001331027.2:c.688T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005327.7:c.676T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hyperinsulinemic hypoglycemia, familial, 4 (HHF4)
Synonyms:
Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency
Identifiers:
MONDO: MONDO:0012382; MedGen: C1864948; Orphanet: 71212; OMIM: 609975

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001999900Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Nov 2, 2021) 		germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Reye-like syndrome resulting from novel missense mutations in mitochondrial medium- and short-chain l-3-hydroxy-acyl-CoA dehydrogenase.

Bennett MJ, Russell LK, Tokunaga C, Narayan SB, Tan L, Seegmiller A, Boriack RL, Strauss AW.

Mol Genet Metab. 2006 Sep-Oct;89(1-2):74-9. Epub 2006 May 24.

PubMed [citation]
PMID:
16725361

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001999900.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024