NM_014845.6(FIG4):c.737G>A (p.Trp246Ter) AND Charcot-Marie-Tooth disease type 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 18, 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:: RCV001232367.7

Allele description [Variation Report for NM_014845.6(FIG4):c.737G>A (p.Trp246Ter)]

NM_014845.6(FIG4):c.737G>A (p.Trp246Ter)

Gene:

FIG4:FIG4 phosphoinositide 5-phosphatase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q21

Genomic location:

Preferred name:

NM_014845.6(FIG4):c.737G>A (p.Trp246Ter)

HGVS:

NC_000006.12:g.109738415G>A
NG_007977.1:g.52195G>A
NM_014845.6:c.737G>AMANE SELECT
NP_055660.1:p.Trp246Ter
NP_055660.1:p.Trp246Ter
LRG_241t1:c.737G>A
LRG_241:g.52195G>A
LRG_241p1:p.Trp246Ter
NC_000006.11:g.110059618G>A
NM_014845.5:c.737G>A

Protein change:

W246*

Links:

dbSNP: rs776005417

NCBI 1000 Genomes Browser:

rs776005417

Molecular consequence:

NM_014845.6:c.737G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Charcot-Marie-Tooth disease type 4
Synonyms:: Charcot-Marie-Tooth, Type 4
Identifiers:: MONDO: MONDO:0018995; MedGen: C4082197

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001404923	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23623387, 30740813, 25614874, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001404923

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 18, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.

Campeau PM, Lenk GM, Lu JT, Bae Y, Burrage L, Turnpenny P, Román Corona-Rivera J, Morandi L, Mora M, Reutter H, Vulto-van Silfhout AT, Faivre L, Haan E, Gibbs RA, Meisler MH, Lee BH.

Am J Hum Genet. 2013 May 2;92(5):781-91. doi: 10.1016/j.ajhg.2013.03.020. Epub 2013 Apr 25.

PubMed [citation]

PMID:: 23623387
PMCID:: PMC3644641

Cerebral hypomyelination associated with biallelic variants of FIG4.

Lenk GM, Berry IR, Stutterd CA, Blyth M, Green L, Vadlamani G, Warren D, Craven I, Fanjul-Fernandez M, Rodriguez-Casero V, Lockhart PJ, Vanderver A, Simons C, Gibb S, Sadedin S; Broad Center for Mendelian Genomics., White SM, Christodoulou J, Skibina O, Ruddle J, Tan TY, Leventer RJ, et al.

Hum Mutat. 2019 May;40(5):619-630. doi: 10.1002/humu.23720. Epub 2019 Feb 28.

PubMed [citation]

PMID:: 30740813
PMCID:: PMC6467804

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001404923.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Trp246*) in the FIG4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FIG4 are known to be pathogenic (PMID: 23623387, 30740813). This variant is present in population databases (rs776005417, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 420149). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as 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: Mar 16, 2024

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