ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 36371492)

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.

Criteria applied: PS4_MOD,PM1,PM2_SUP,PP3

PS3, PS4_Moderate, PM2, PP2, PP3

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Loss-of-function variants and missense within the RhoGEF domain are associated with microcephaly while gain-of-function missense within the 7th spectrin repeat are associated with macrocephaly (PMID: 32109419). (N) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. THis variant is in exon 29 of the TRIO gene. (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif. In the RhoGEF domain (NCBI, DECIPHER). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported to be de novo in one patient with microcephaly (DECIPHER). (P) 0905 - No segregation evidence has been identified for this variant in the literature. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

The p.Asn1465Ser variant in the TRIO gene was identified de novo in this individual, but has not been previously reported in association with disease. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Asn1465Ser variant is located in the DH1 subdomain of TRIO. Other pathogenic and likely pathogenic variants have been described in this domain and disrupt the function of TRIO. The TRIO gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that the p.Asn1465Ser variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Asn1465Ser variant as likely pathogenic for TRIO-associated intellectual disability in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2_moderate; PM2; PP2; PP3]

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.