NM_014845.6(FIG4):c.2433AGA[2] (p.Glu813del) AND Cerebral hypomyelination

Clinical significance:Likely pathogenic (Last evaluated: May 28, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001254717.1

Allele description [Variation Report for NM_014845.6(FIG4):c.2433AGA[2] (p.Glu813del)]

NM_014845.6(FIG4):c.2433AGA[2] (p.Glu813del)

Gene:
FIG4:FIG4 phosphoinositide 5-phosphatase [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
6q21
Genomic location:
Preferred name:
NM_014845.6(FIG4):c.2433AGA[2] (p.Glu813del)
HGVS:
  • NC_000006.12:g.109792638AGA[2]
  • NG_007977.1:g.106418AGA[2]
  • NM_014845.6:c.2433AGA[2]MANE SELECT
  • NP_055660.1:p.Glu813del
  • LRG_241t1:c.2433_2435AGA[2]
  • LRG_241:g.106418AGA[2]
  • NC_000006.11:g.110113841AGA[2]
  • NC_000006.12:g.109792638_109792640AGA[2]
  • NM_014845.5(FIG4):c.2433_2435AGA[2]
  • NM_014845.5:c.2439_2441delAGA
  • p.Glu813del
Protein change:
E813del
Links:
dbSNP: rs876661144
NCBI 1000 Genomes Browser:
rs876661144
Molecular consequence:
  • NM_014845.6:c.2433AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

Name:
Cerebral hypomyelination
Synonyms:
Hypomyelination of the brain
Identifiers:
MedGen: C2677328; Human Phenotype Ontology: HP:0006808

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001430790Broad Institute Rare Disease Group, Broad Institutecriteria provided, single submitter
Likely pathogenic
(May 28, 2020)
germlineresearch

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 providedresearch

Citations

PubMed

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

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 Broad Institute Rare Disease Group, Broad Institute, SCV001430790.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (2)

Description

The heterozygous p.Glu813del variant in FIG4 was identified by our study, in the compound heterozygous state, along with another likely pathogenic variant, in 3 siblings with cerebral hypomyelination (PMID: 30740813). This variant has also been reported as a VUS by GeneDx in ClinVar (Variation ID: 234659). This variant has been identified in 0.003% (1/34550) of Latino chromosomes and 0.002% (2/113662) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs876661144). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Glu813del variant may slightly impact protein function (PMID: 30740813). However, these types of assays may not accurately represent biological function. This variant is a deletion of 1 amino acid at position 813 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. The presence of this variant in combination with a likely pathogenic variant and in 3 siblings with cerebral hypomyelination increases the likelihood that the p.Glu813del variant is pathogenic (PMID: 30740813). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PM4_Supporting, PP1, PS3_Supporting (Richards 2015).

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

Last Updated: May 28, 2021

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