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NM_001079866.2(BCS1L):c.325C>T (p.Arg109Trp) AND GRACILE syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 21, 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:
RCV003226245.1

Allele description [Variation Report for NM_001079866.2(BCS1L):c.325C>T (p.Arg109Trp)]

NM_001079866.2(BCS1L):c.325C>T (p.Arg109Trp)

Gene:
BCS1L:BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q35
Genomic location:
Preferred name:
NM_001079866.2(BCS1L):c.325C>T (p.Arg109Trp)
Other names:
p.R109W:CGG>TGG
HGVS:
  • NC_000002.12:g.218661410C>T
  • NG_008018.1:g.6755C>T
  • NG_033099.1:g.3131G>A
  • NM_001079866.2:c.325C>TMANE SELECT
  • NM_001257342.2:c.325C>T
  • NM_001257343.2:c.325C>T
  • NM_001257344.2:c.325C>T
  • NM_001318836.2:c.-36C>T
  • NM_001320717.2:c.325C>T
  • NM_001371443.1:c.325C>T
  • NM_001371444.1:c.325C>T
  • NM_001371446.1:c.325C>T
  • NM_001371447.1:c.325C>T
  • NM_001371448.1:c.325C>T
  • NM_001371449.1:c.325C>T
  • NM_001371450.1:c.325C>T
  • NM_001371451.1:c.-36C>T
  • NM_001371452.1:c.-41-349C>T
  • NM_001371453.1:c.-152C>T
  • NM_001371454.1:c.-152C>T
  • NM_001371455.1:c.-152C>T
  • NM_001371456.1:c.-152C>T
  • NM_001374085.1:c.325C>T
  • NM_001374086.1:c.-152C>T
  • NM_004328.5:c.325C>T
  • NP_001073335.1:p.Arg109Trp
  • NP_001244271.1:p.Arg109Trp
  • NP_001244272.1:p.Arg109Trp
  • NP_001244273.1:p.Arg109Trp
  • NP_001307646.1:p.Arg109Trp
  • NP_001358372.1:p.Arg109Trp
  • NP_001358373.1:p.Arg109Trp
  • NP_001358375.1:p.Arg109Trp
  • NP_001358376.1:p.Arg109Trp
  • NP_001358377.1:p.Arg109Trp
  • NP_001358378.1:p.Arg109Trp
  • NP_001358379.1:p.Arg109Trp
  • NP_001361014.1:p.Arg109Trp
  • NP_004319.1:p.Arg109Trp
  • NP_004319.1:p.Arg109Trp
  • LRG_539t1:c.325C>T
  • LRG_539:g.6755C>T
  • LRG_539p1:p.Arg109Trp
  • NC_000002.11:g.219526133C>T
  • NM_004328.4:c.325C>T
  • NR_163955.1:n.1337C>T
Protein change:
R109W
Links:
dbSNP: rs141257714
NCBI 1000 Genomes Browser:
rs141257714
Molecular consequence:
  • NM_001318836.2:c.-36C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001371451.1:c.-36C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001371453.1:c.-152C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001371454.1:c.-152C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001371455.1:c.-152C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001371456.1:c.-152C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001374086.1:c.-152C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001371452.1:c.-41-349C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001079866.2:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001257342.2:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001257343.2:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001257344.2:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320717.2:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001371443.1:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001371444.1:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001371446.1:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001371447.1:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001371448.1:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001371449.1:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001371450.1:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374085.1:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004328.5:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_163955.1:n.1337C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
GRACILE syndrome (FLNMS)
Synonyms:
Finnish lactic acidosis with hepatic hemosiderosis; Fellman syndrome; Growth Retardation, Aminoaciduria, Cholestasis, Iron overload, Lactic acidosis and Early death; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0011308; MedGen: C1864002; Orphanet: 53693; OMIM: 603358

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV003922925Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Mar 21, 2023)
germlineclinical testing

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

Citation Link

Summary from all submissions

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

Citations

PubMed

Expanding the phenotypic spectrum of BCS1L-related mitochondrial disease.

Hikmat O, Isohanni P, Keshavan N, Ferla MP, Fassone E, Abbott MA, Bellusci M, Darin N, Dimmock D, Ghezzi D, Houlden H, Invernizzi F, Kamarus Jaman NB, Kurian MA, Morava E, Naess K, Ortigoza-Escobar JD, Parikh S, Pennisi A, Barcia G, Tylleskär KB, Brackman D, et al.

Ann Clin Transl Neurol. 2021 Nov;8(11):2155-2165. doi: 10.1002/acn3.51470. Epub 2021 Oct 18.

PubMed [citation]
PMID:
34662929
PMCID:
PMC8607453

Molecular genetic investigations identify new clinical phenotypes associated with BCS1L-related mitochondrial disease.

Oláhová M, Ceccatelli Berti C, Collier JJ, Alston CL, Jameson E, Jones SA, Edwards N, He L, Chinnery PF, Horvath R, Goffrini P, Taylor RW, Sayer JA.

Hum Mol Genet. 2019 Nov 15;28(22):3766-3776. doi: 10.1093/hmg/ddz202.

PubMed [citation]
PMID:
31435670
PMCID:
PMC6935384

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003922925.1

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

Description

Variant summary: BCS1L c.325C>T (p.Arg109Trp) results in a non-conservative amino acid change located in the BCS1, N-terminal domain (IPR014851) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251486 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BCS1L causing GRACILE Syndrome (4.4e-05 vs 0.00047), allowing no conclusion about variant significance. c.325C>T has been reported in the literature in at least three homozygous individuals, 2 of whom were siblings, affected with GRACILE Syndrome (Olahova_2019, Hikmat_2021). These data indicate that the variant is very likely to be associated with disease. Yeast complementation studies showed that the variant was not able to rescue oxidative phosphorylation in a BCS1L deficient yeast strain, indicating loss of function (Olahova_2019). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Jun 17, 2024