NM_001370298.3(FGD4):c.1276C>T (p.Leu426Phe) AND Charcot-Marie-Tooth disease type 4

Clinical significance:Uncertain significance (Last evaluated: Jul 13, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_001370298.3(FGD4):c.1276C>T (p.Leu426Phe)]

NM_001370298.3(FGD4):c.1276C>T (p.Leu426Phe)

FGD4:FYVE, RhoGEF and PH domain containing 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_001370298.3(FGD4):c.1276C>T (p.Leu426Phe)
  • NC_000012.12:g.32602189C>T
  • NG_008626.2:g.207661C>T
  • NM_001304481.1:c.1120C>T
  • NM_001304483.2:c.121C>T
  • NM_001304484.2:c.-187C>T
  • NM_001330373.2:c.586C>T
  • NM_001330374.2:c.586C>T
  • NM_001370297.1:c.313C>T
  • NM_001370298.3:c.1276C>TMANE SELECT
  • NM_001384126.1:c.1276C>T
  • NM_001384127.1:c.865C>T
  • NM_001384128.1:c.865C>T
  • NM_001384130.1:c.586C>T
  • NM_001385118.1:c.865C>T
  • NM_139241.3:c.865C>T
  • NP_001291410.1:p.Leu374Phe
  • NP_001291412.1:p.Leu41Phe
  • NP_001317302.1:p.Leu196Phe
  • NP_001317303.1:p.Leu196Phe
  • NP_001357226.1:p.Leu105Phe
  • NP_001357227.2:p.Leu426Phe
  • NP_001371055.1:p.Leu426Phe
  • NP_001371056.1:p.Leu289Phe
  • NP_001371057.1:p.Leu289Phe
  • NP_001371059.1:p.Leu196Phe
  • NP_001372047.1:p.Leu289Phe
  • NP_640334.2:p.Leu289Phe
  • LRG_240t1:c.865C>T
  • LRG_240t2:c.1120C>T
  • LRG_240:g.207661C>T
  • LRG_240p1:p.Leu289Phe
  • LRG_240p2:p.Leu374Phe
  • NC_000012.11:g.32755123C>T
Protein change:
Molecular consequence:
  • NM_001304484.2:c.-187C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001304481.1:c.1120C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001304483.2:c.121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330373.2:c.586C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330374.2:c.586C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370297.1:c.313C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370298.3:c.1276C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001384126.1:c.1276C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001384127.1:c.865C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001384128.1:c.865C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001384130.1:c.586C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001385118.1:c.865C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139241.3:c.865C>T - missense variant - [Sequence Ontology: SO:0001583]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001561413Invitaecriteria provided, single submitter
Uncertain significance
(Jul 13, 2020)
germlineclinical testing

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

Summary from all submissions

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



Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Details of each submission

From Invitae, SCV001561413.1

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


This sequence change replaces leucine with phenylalanine at codon 289 of the FGD4 protein (p.Leu289Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FGD4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C1). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5

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

Last Updated: Oct 7, 2021

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