NM_001278716.2(FBXL4):c.1622C>T (p.Thr541Ile) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 27, 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:: RCV003155218.1

Allele description [Variation Report for NM_001278716.2(FBXL4):c.1622C>T (p.Thr541Ile)]

NM_001278716.2(FBXL4):c.1622C>T (p.Thr541Ile)

Gene:

FBXL4:F-box and leucine rich repeat protein 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q16.1

Genomic location:

Preferred name:

NM_001278716.2(FBXL4):c.1622C>T (p.Thr541Ile)

HGVS:

NC_000006.12:g.98875495G>A
NG_033903.1:g.77512C>T
NM_001278716.2:c.1622C>TMANE SELECT
NM_012160.5:c.1622C>T
NP_001265645.1:p.Thr541Ile
NP_036292.2:p.Thr541Ile
NP_036292.2:p.Thr541Ile
NC_000006.11:g.99323371G>A
NM_012160.4:c.1622C>T
NR_103836.2:n.1607C>T

Protein change:

T541I

Links:

dbSNP: rs1391578014

NCBI 1000 Genomes Browser:

rs1391578014

Molecular consequence:

NM_001278716.2:c.1622C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012160.5:c.1622C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_103836.2:n.1607C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003844281	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28940506, 30804983, 27743463 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003844281

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 27, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular and clinical spectra of FBXL4 deficiency.

El-Hattab AW, Dai H, Almannai M, Wang J, Faqeih EA, Al Asmari A, Saleh MAM, Elamin MAO, Alfadhel M, Alkuraya FS, Hashem M, Aldosary MS, Almass R, Almutairi FB, Alsagob M, Al-Owain M, Al-Sharfa S, Al-Hassnan ZN, Rahbeeni Z, Al-Muhaizea MA, Makhseed N, Foskett GK, et al.

Hum Mutat. 2017 Dec;38(12):1649-1659. doi: 10.1002/humu.23341. Epub 2017 Oct 6. Review.

PubMed [citation]

PMID:: 28940506

Ballout RA, Al Alam C, Bonnen PE, Huemer M, El-Hattab AW, Shbarou R.

Front Genet. 2019;10:39. doi: 10.3389/fgene.2019.00039.

PubMed [citation]

PMID:: 30804983
PMCID:: PMC6370620

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844281.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: FBXL4 c.1622C>T (p.Thr541Ile) results in a non-conservative amino acid change located in the Leucine-Rich Repeats (El-Hattab_2017) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251002 control chromosomes (gnomAD). c.1622C>T has been reported in the literature in individuals affected with lactic acidemia and mitochondrial disorder (Dai_2017, El-Hattab_2017, Ballout_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites this variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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