NM_000017.4(ACADS):c.1095G>T (p.Gln365His) AND Deficiency of butyryl-CoA dehydrogenase

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Jul 12, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000411694.6

Allele description [Variation Report for NM_000017.4(ACADS):c.1095G>T (p.Gln365His)]

NM_000017.4(ACADS):c.1095G>T (p.Gln365His)

Gene:
ACADS:acyl-CoA dehydrogenase short chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q24.31
Genomic location:
Preferred name:
NM_000017.4(ACADS):c.1095G>T (p.Gln365His)
Other names:
p.Q365H:CAG>CAT
HGVS:
  • NC_000012.12:g.120739304G>T
  • NG_007991.1:g.18537G>T
  • NM_000017.4:c.1095G>TMANE SELECT
  • NM_001302554.2:c.1083G>T
  • NP_000008.1:p.Gln365His
  • NP_001289483.1:p.Gln361His
  • NC_000012.11:g.121177107G>T
  • NM_000017.2:c.1095G>T
  • NM_000017.3:c.1095G>T
Protein change:
Q361H
Links:
dbSNP: rs368469075
NCBI 1000 Genomes Browser:
rs368469075
Molecular consequence:
  • NM_000017.4:c.1095G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001302554.2:c.1083G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Deficiency of butyryl-CoA dehydrogenase (ACADSD)
Synonyms:
ACYL-CoA DEHYDROGENASE, SHORT-CHAIN, DEFICIENCY OF; Lipid-storage myopathy secondary to short chain acyl CoA dehydrogenase deficiency; SCAD DEFICIENCY, MILD
Identifiers:
MONDO: MONDO:0008722; MedGen: C0342783; Orphanet: 26792; OMIM: 201470

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000486661Counsylno assertion criteria providedLikely pathogenic
(Jul 21, 2016)
unknownclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000914567Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely pathogenic
(Jan 10, 2019)
germlineclinical testing

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

Citation Link,

SCV000952058Invitaecriteria provided, single submitter
Uncertain significance
(Jul 12, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Clinical outcomes of infants with short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD) detected by newborn screening.

Jethva R, Ficicioglu C.

Mol Genet Metab. 2008 Dec;95(4):241-2. doi: 10.1016/j.ymgme.2008.09.003. Epub 2008 Oct 23. No abstract available.

PubMed [citation]
PMID:
18951053

Follow-up of patients with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening: one center's experience.

Pena L, Angle B, Burton B, Charrow J.

Genet Med. 2012 Mar;14(3):342-7. doi: 10.1038/gim.2011.9. Epub 2012 Jan 5.

PubMed [citation]
PMID:
22241096
See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000486661.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000914567.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The ACADS c.1095G>T (p.Gln365His) missense variant has been reported in two studies in which it is found in a compound heterozygous state with another missense variant in two probands with short-chain acyl-coA dehydrogenase (SCAD) deficiency (Seidel et al. 2003; Pedersen et al. 2008). The p.Gln365His variant was absent from 100 control alleles and is reported at a frequency of 0.000128 in the African population of the Genome Aggregation Database. Functional studies in vitro revealed that the p.Gln365His variant was found to translate and import into mitochondria efficiently but had a decreased ability to form the mature tetrameric enzyme leading to misfolding, and a severe increased tendency to form aggregates especially at an elevated temperature (Seidel et al. 2003; Pedersen et al. 2008). Based on the evidence, the p.Gln365His variant is classified as likely pathogenic for short-chain acyl-coA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

From Invitae, SCV000952058.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces glutamine with histidine at codon 365 of the ACADS protein (p.Gln365His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs368469075, ExAC 0.01%). This variant has been observed in an individual affected with SCAD deficiency (PMID: 12872838). This variant is also known as Gln341His in the literature. ClinVar contains an entry for this variant (Variation ID: 203560). Experimental studies have shown that this missense change causes a defect in protein folding (PMID: 14506246). 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.

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

Last Updated: Mar 22, 2021

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