NM_007118.4(TRIO):c.4394A>G (p.Asn1465Ser) AND TRIO-related disorder

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jul 3, 2023
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:: RCV002508954.4

Allele description [Variation Report for NM_007118.4(TRIO):c.4394A>G (p.Asn1465Ser)]

NM_007118.4(TRIO):c.4394A>G (p.Asn1465Ser)

Gene:

TRIO:trio Rho guanine nucleotide exchange factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5p15.2

Genomic location:

Preferred name:

NM_007118.4(TRIO):c.4394A>G (p.Asn1465Ser)

HGVS:

NC_000005.10:g.14397125A>G
NG_052962.1:g.258424A>G
NM_007118.4:c.4394A>GMANE SELECT
NP_009049.2:p.Asn1465Ser
NC_000005.9:g.14397234A>G
NM_007118.2:c.4394A>G
NM_007118.3:c.4394A>G
NR_134469.2:n.4778A>G
p.Asn1465Ser

Protein change:

N1465S

Links:

dbSNP: rs1747669042

NCBI 1000 Genomes Browser:

rs1747669042

Molecular consequence:

NM_007118.4:c.4394A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_134469.2:n.4778A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: TRIO-related disorder
Synonyms:: TRIO-related condition; TRIO-Related Disorders
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002818390	GenomeConnect, ClinGen	no classification provided	not provided	de novo	phenotyping only
SCV003928328	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 6, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004099111	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 3, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002818390

GenomeConnect, ClinGen

no classification provided

not provided

de novo

phenotyping only

SCV003928328

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 6, 2023)

germline

clinical testing

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

Citation Link,

SCV004099111

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 3, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	phenotyping only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature.

Gazdagh G, Hunt D, Gonzalez AMC, Rodriguez MP, Chaudhry A, Madruga M, Vansenne F, Shears D, Curie A, Stattin EL, Anderlid BM, Trajkova S, Angelovska ES, McWilliam C, Wyatt PR, O'Driscoll M, Atton G, Bergman AK, Zacher P, Mewasingh LD, López AG, Alonso-Luengo O, et al.

Am J Med Genet A. 2023 Jul;191(7):1722-1740. doi: 10.1002/ajmg.a.63194. Epub 2023 Mar 29. Review.

PubMed [citation]

PMID:: 36987741

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 GenomeConnect, ClinGen, SCV002818390.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant classified as Pathogenic and reported on 08-27-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003928328.1

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

Description

Variant summary: TRIO c.4394A>G (p.Asn1465Ser) results in a conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 242190 control chromosomes (gnomAD). c.4394A>G has been reported in the literature in individuals affected with TRIO-Related Intellectual Disability (Gazdagh_2023). These data indicate that the variant may be associated with disease. The variant protein was confirmed as to be Loss-of-Function since it could not activate RAC1, performing identically to a non-functional form of TRIO (Gazdagh_2023). Four ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was 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

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV004099111.1

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

Description

PS3, PS4_Moderate, PM2, PP2, PP3

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

Last Updated: Nov 24, 2024

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