NM_001278716.2(FBXL4):c.1652T>A (p.Ile551Asn) AND Mitochondrial DNA depletion syndrome 13

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 5, 2020
Review status:: criteria provided, conflicting classifications

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:: RCV000502490.5

Allele description [Variation Report for NM_001278716.2(FBXL4):c.1652T>A (p.Ile551Asn)]

NM_001278716.2(FBXL4):c.1652T>A (p.Ile551Asn)

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.1652T>A (p.Ile551Asn)

HGVS:

NC_000006.12:g.98875465A>T
NG_033903.1:g.77542T>A
NM_001278716.2:c.1652T>AMANE SELECT
NM_012160.5:c.1652T>A
NP_001265645.1:p.Ile551Asn
NP_036292.2:p.Ile551Asn
NP_036292.2:p.Ile551Asn
NC_000006.11:g.99323341A>T
NM_012160.4:c.1652T>A
NR_103836.2:n.1637T>A

Protein change:

I551N

Links:

dbSNP: rs1554215979

NCBI 1000 Genomes Browser:

rs1554215979

Molecular consequence:

NM_001278716.2:c.1652T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012160.5:c.1652T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_103836.2:n.1637T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mitochondrial DNA depletion syndrome 13
Synonyms:: Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type)
Identifiers:: MONDO: MONDO:0014198; MedGen: C3809592; Orphanet: 369897; OMIM: 615471

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000598172	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 10, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23993194, 25741868
SCV001519808	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 5, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000598172

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 10, 2017)

germline

clinical testing

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

SCV001519808

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 5, 2020)

unknown

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.

Gai X, Ghezzi D, Johnson MA, Biagosch CA, Shamseldin HE, Haack TB, Reyes A, Tsukikawa M, Sheldon CA, Srinivasan S, Gorza M, Kremer LS, Wieland T, Strom TM, Polyak E, Place E, Consugar M, Ostrovsky J, Vidoni S, Robinson AJ, Wong LJ, Sondheimer N, et al.

Am J Hum Genet. 2013 Sep 5;93(3):482-95. doi: 10.1016/j.ajhg.2013.07.016. Epub 2013 Aug 29.

PubMed [citation]

PMID:: 23993194
PMCID:: PMC3769923

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 Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000598172.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The NM_012160.4:c.1652T>A (NP_036292.2:p.Ile551Asn) [GRCH38: NC_000006.12:g.98875465A>T] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993194 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PS3:A well established functional studies show a deleterious effect on FBXL4. PM2:This variant is absent in key population databases. PP2:This is a missense variant in FBXL4 with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FBXL4 structure, function, or protein-protein interaction. PP4:Patientâ€™s phenotype or family history is highly specific for FBXL4. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Pathogenic.

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

From Baylor Genetics, SCV001519808.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

Last Updated: Jun 23, 2024

ClinVar

Relating variation to medicine