NM_001111125.3(IQSEC2):c.2911C>T (p.Arg971Ter) AND Intellectual disability, X-linked 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 17, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001385379.10

Allele description [Variation Report for NM_001111125.3(IQSEC2):c.2911C>T (p.Arg971Ter)]

NM_001111125.3(IQSEC2):c.2911C>T (p.Arg971Ter)

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.2911C>T (p.Arg971Ter)

HGVS:

NC_000023.11:g.53241888G>A
NG_021296.2:g.84463C>T
NM_001111125.3:c.2911C>TMANE SELECT
NM_015075.2:c.2296C>T
NP_001104595.1:p.Arg971Ter
NP_055890.1:p.Arg766Ter
LRG_1194t1:c.2911C>T
LRG_1194:g.84463C>T
LRG_1194p1:p.Arg971Ter
NC_000023.10:g.53271070G>A
NM_001111125.1:c.2911C>T
NM_001111125.2:c.2911C>T

Protein change:

R766*

Links:

dbSNP: rs1131691887

NCBI 1000 Genomes Browser:

rs1131691887

Molecular consequence:

NM_001111125.3:c.2911C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_015075.2:c.2296C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001585214	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21686261, 26793055, 27665735, 30666632, 28492532
SCV003841658	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30666632, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001585214

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 17, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV003841658

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 23, 2023)

unknown

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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Subtle functional defects in the Arf-specific guanine nucleotide exchange factor IQSEC2 cause non-syndromic X-linked intellectual disability.

Shoubridge C, Walikonis RS, Gécz J, Harvey RJ.

Small GTPases. 2010 Sep;1(2):98-103.

PubMed [citation]

PMID:: 21686261
PMCID:: PMC3116596

Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family.

Kalscheuer VM, James VM, Himelright ML, Long P, Oegema R, Jensen C, Bienek M, Hu H, Haas SA, Topf M, Hoogeboom AJ, Harvey K, Walikonis R, Harvey RJ.

Front Mol Neurosci. 2015;8:85. doi: 10.3389/fnmol.2015.00085.

PubMed [citation]

PMID:: 26793055
PMCID:: PMC4707274

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001585214.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Arg971*) in the IQSEC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IQSEC2 are known to be pathogenic (PMID: 21686261, 26793055, 27665735). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of IQSEC2-related conditions (PMID: 30666632). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430286). 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

From 3billion, SCV003841658.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000430286 / PMID: 30666632). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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