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NM_000018.4(ACADVL):c.553G>A (p.Gly185Ser) AND ACADVL-related disorder

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 12, 2023
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:
RCV003416111.4

Allele description [Variation Report for NM_000018.4(ACADVL):c.553G>A (p.Gly185Ser)]

NM_000018.4(ACADVL):c.553G>A (p.Gly185Ser)

Gene:
ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000018.4(ACADVL):c.553G>A (p.Gly185Ser)
Other names:
p.G185S:GGT>AGT; NM_000018.4(ACADVL):c.553G>A
HGVS:
  • NC_000017.11:g.7221613G>A
  • NG_007975.1:g.6780G>A
  • NG_008391.2:g.3438C>T
  • NM_000018.4:c.553G>AMANE SELECT
  • NM_001033859.3:c.487G>A
  • NM_001270447.2:c.622G>A
  • NM_001270448.2:c.325G>A
  • NP_000009.1:p.Gly185Ser
  • NP_001029031.1:p.Gly163Ser
  • NP_001257376.1:p.Gly208Ser
  • NP_001257377.1:p.Gly109Ser
  • NP_001257377.1:p.Gly109Ser
  • NC_000017.10:g.7124932G>A
  • NM_000018.2:c.553G>A
  • NM_000018.3:c.553G>A
  • NM_000018.4:c.553G>A
  • NM_001033859.1:c.487G>A
  • NM_001270448.1:c.325G>A
  • P49748:p.Gly185Ser
Protein change:
G109S
Links:
UniProtKB: P49748#VAR_000335; dbSNP: rs545215807
NCBI 1000 Genomes Browser:
rs545215807
Molecular consequence:
  • NM_000018.4:c.553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001033859.3:c.487G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270447.2:c.622G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001270448.2:c.325G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
ACADVL-related disorder
Synonyms:
ACADVL-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004113809PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(May 12, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

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 PreventionGenetics, part of Exact Sciences, SCV004113809.1

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

Description

The ACADVL c.553G>A variant is predicted to result in the amino acid substitution p.Gly185Ser. This variant has been reported, along with a second ACADVL variant, in patients with very long chain acyl-CoA dehydrogenase deficiency (VLCADD) ranging from the severe neonatal onset form to later onset exercise-induced rhabdomyolysis (Gobin-Limballe et al. 2007. PubMed ID: 17999356; Yamaguchi et al. 2012. PubMed ID: 22841441; Musumeci et al. 2020. PubMed ID: 32655480). It was also reported in the heterozygous state without a second ACADVL variant in a patient with 29% residual enzyme activity (Hoffmann et al. 2012. PubMed ID: 21932095, described as p.G145S). In fibroblasts from patients carrying the p.Gly185Ser substitution along with a second ACADVL variant, enzyme activity and protein levels were greatly reduced (Gobin-Limballe et al. 2007. PubMed ID: 17999356; Gobin-Limballe et al. 2010. PubMed ID: 20060901). Based on structure mapping, the p.Gly185 amino acid is predicted to lie in a very hydrophobic pocket lining the enzyme acyl-CoA binding cavity, and it has been noted that substitution of glycine with a polar serine residue in this location could affect substrate binding (Gobin-Limballe et al. 2010. PubMed ID: 20060901). This variant has been interpreted as likely pathogenic by the ClinGen ACADVL Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/203595/). Taken together, we interpret the c.553G>A (p.Gly185Ser) variant as likely pathogenic for autosomal recessive VLCADD.

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

Last Updated: Oct 20, 2024