NM_001111125.3(IQSEC2):c.2983C>T (p.Arg995Trp) AND Intellectual disability, X-linked 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 28, 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:: RCV001048074.10

Allele description [Variation Report for NM_001111125.3(IQSEC2):c.2983C>T (p.Arg995Trp)]

NM_001111125.3(IQSEC2):c.2983C>T (p.Arg995Trp)

Gene:

IQSEC2:IQ motif and Sec7 domain ArfGEF 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.22

Genomic location:

Preferred name:

NM_001111125.3(IQSEC2):c.2983C>T (p.Arg995Trp)

HGVS:

NC_000023.11:g.53241816G>A
NG_021296.2:g.84535C>T
NM_001111125.3:c.2983C>TMANE SELECT
NM_015075.2:c.2368C>T
NP_001104595.1:p.Arg995Trp
NP_055890.1:p.Arg790Trp
LRG_1194t1:c.2983C>T
LRG_1194:g.84535C>T
LRG_1194p1:p.Arg995Trp
NC_000023.10:g.53270998G>A
NM_001111125.1:c.2983C>T
NM_001111125.2:c.2983C>T

Protein change:

R790W

Links:

dbSNP: rs1057521657

NCBI 1000 Genomes Browser:

rs1057521657

Molecular consequence:

NM_001111125.3:c.2983C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_015075.2:c.2368C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Intellectual disability, X-linked 1 (XLID1)
Synonyms:: Mental retardation, X-linked, nonspecific; Atkin Flaitz Patil Smith syndrome; MENTAL RETARDATION, X-LINKED 18; See all synonyms [MedGen]
Identifiers:: Gene: 170530; MONDO: MONDO:0010656; MedGen: C2931498; Orphanet: 777; OMIM: 309530

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001212063	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29322350, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001212063

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 28, 2023)

germline

clinical testing

PubMed (2)
[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

Monogenic disorders that mimic the phenotype of Rett syndrome.

Srivastava S, Desai S, Cohen J, Smith-Hicks C, Barañano K, Fatemi A, Naidu S.

Neurogenetics. 2018 Jan;19(1):41-47. doi: 10.1007/s10048-017-0535-3. Epub 2018 Jan 10.

PubMed [citation]

PMID:: 29322350
PMCID:: PMC6156085

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001212063.5

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 995 of the IQSEC2 protein (p.Arg995Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with global developmental delay, hypotonia, and language regression (PMID: 29322350). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 383534). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IQSEC2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Sep 29, 2024

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