NM_001111125.3(IQSEC2):c.2777G>A (p.Arg926Gln) AND Intellectual disability, X-linked 1

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Feb 16, 2024
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:: RCV000647966.12

Allele description [Variation Report for NM_001111125.3(IQSEC2):c.2777G>A (p.Arg926Gln)]

NM_001111125.3(IQSEC2):c.2777G>A (p.Arg926Gln)

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.2777G>A (p.Arg926Gln)

HGVS:

NC_000023.11:g.53243444C>T
NG_021296.2:g.82907G>A
NM_001111125.3:c.2777G>AMANE SELECT
NM_015075.2:c.2162G>A
NP_001104595.1:p.Arg926Gln
NP_055890.1:p.Arg721Gln
LRG_1194t1:c.2777G>A
LRG_1194:g.82907G>A
LRG_1194p1:p.Arg926Gln
NC_000023.10:g.53272626C>T
NM_001111125.2:c.2777G>A

Protein change:

R721Q

Links:

dbSNP: rs1556861372

NCBI 1000 Genomes Browser:

rs1556861372

Molecular consequence:

NM_001111125.3:c.2777G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_015075.2:c.2162G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Intellectual disability, X-linked 1 (XLID1)
Synonyms:: Atkin Flaitz Patil Smith syndrome; MENTAL RETARDATION, X-LINKED 18; MENTAL RETARDATION, X-LINKED 78; 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
SCV000769776	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Feb 16, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002557888	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20473311, 30206421, 30842726, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000769776

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Feb 16, 2024)

germline

clinical testing

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

SCV002557888

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 2, 2022)

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

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

Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability.

Shoubridge C, Tarpey PS, Abidi F, Ramsden SL, Rujirabanjerd S, Murphy JA, Boyle J, Shaw M, Gardner A, Proos A, Puusepp H, Raymond FL, Schwartz CE, Stevenson RE, Turner G, Field M, Walikonis RS, Harvey RJ, Hackett A, Futreal PA, Stratton MR, Gécz J.

Nat Genet. 2010 Jun;42(6):486-8. doi: 10.1038/ng.588. Epub 2010 May 16.

PubMed [citation]

PMID:: 20473311
PMCID:: PMC3632837

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000769776.4

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

#	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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557888.3

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanism of disease in this gene and are associated with IQSEC2-related intellectual disability (MIM# 309530). Loss of function has been demonstrated as the predominant disease mechanism for this gene, however some missense variants have been shown to impair GTP binding and cause the constitutively active protein activity (PMID: 20473311, PMID: 30842726). (I) 0110 - This gene is associated with X-linked disease. Males present with a severe early-onset condition, whereas females have a more variable phenotype, which tends be milder with a later onset, and they can also be asymptomatic carriers (PMID: 30206421). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0253 - This variant is hemizygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a X-linked condition (2 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Sec7 domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has previously been classified as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: May 25, 2025

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Relating variation to medicine