ClinVar Genomic variation as it relates to human health

This variant is interpreted as Likely pathogenic for Intellectual developmental disorder, autosomal recessive 67. The following ACMG Tag(s) were applied: PM2, PP3, PS3-Moderate, PM3.

The variant c.694T>G, p.(Phe232Val) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was M + P.The variant likely explains the NDD in this individual.

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2.

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000617475, PMID:30409806, PS1_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000711, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.759, 3CNET: 0.883, PP3_P). A missense variant is a common mechanism associated with Mental retardation (PP2_P). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID:30409806, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

This variant was identified as homozygous._x000D_ Criteria applied: PM3_VSTR, PS3, PM1_STR

Variant summary: EIF3F c.694T>G (p.Phe232Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 251224 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. c.694T>G has been reported in the literature in multiple homozygous individuals and at least one compound heterozygous individual affected with Autosomal Recessive Intellectual Developmental Disorder from at least 23 different families (e.g. Martin_2018, Huffmeier_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in reduced protein expression, approximately 70% of WT, and was associated with reduced protein translation and cellular proliferation rates (Martin_2018). Haplotype analyses have suggested that c.694T>G may be a common founder variant within populations of European ancestry (Huffmeier_2021). Fifteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as either pathogenic (n=10) or likely pathogenic (n=4), and one classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.

PS3, PM3_Strong, PP3

The EIF3F c.694T>G (p.Phe232Val) variant has been published in the compound heterozygous or homozygous state in at least 21 individuals with intellectual disability ranging from mild to moderate, and approximately half of affected individuals also displayed behavioral problems, hearing loss, and short stature (Hüffmeier U et al., PMID: 33736665; Martin HC et al., PMID: 30409806). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by 19 submitters. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.12% in the European (non-Finnish) population and this variant has been implicated as a founder variant (Hüffmeier U et al., PMID: 33736665). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to EIF3F3 function. In support of this prediction, functional studies show that this variant causes reduced global translation and impairs cellular proliferation (Martin HC et al., PMID: 30409806). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Criteria Codes: PS3_Mod PP1_Str PP3

The c.694T>G (p.F232V) alteration is located in coding exon 5 of the EIF3F gene. This alteration results from a T to G substitution at nucleotide position 694, causing the phenylalanine (F) at amino acid position 232 to be replaced by a valine (V). Based on data from gnomAD, the G allele has an overall frequency of 0.07% (201/282630) total alleles studied. The highest observed frequency was 0.21% (22/10366) of Ashkenazi Jewish alleles. This alteration was reported in the homozygous state in 9 individuals from 7 families; each individual had intellectual disability, and the presence of additional features, including seizures, behavioral difficulties, and sensorineural hearing loss were variable (Martin, 2018). An additional 21 individuals from 16 families were recently reported to be homozygous or compound heterozygous, suggesting that this alteration is a founder mutation in the Ashkenazi Jewish and non-Finnish European populations (Hüffmeier, 2021). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.F232V alteration resulted in impaired translation and decreased induced pluripotent stem cell (iPSC) cell proliferation; iPSCs homozygous for this alteration showed lower EIF3F protein expression compared to heterozygous and wild-type cells (Martin, 2018). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Intellectual developmental disorder, autosomal recessive 67 (MIM#618295). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to valine. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (201 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (highest allele count (v3): 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar and has been observed in many homozygous and at least one compound heterozygous individual with a neurodevelopmental disorder (PMID: 33736665). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

EIF3F: PM3:Strong, PP1:Strong, PM1, PM2, PP3, PS3:Supporting

The EIF3F c.694T>G variant is predicted to result in the amino acid substitution p.Phe232Val. This variant has been reported in the homozygous state in nine individuals with intellectual disability and a subset with seizures, behavioral difficulties, and sensorineural hearing loss (Table S5, Martin et al. 2018. PubMed ID: 30409806). In the same study, the authors showed that this variant leads to ~27% lower EIF3F protein levels compared to wild type EIF3F protein, and reduced translation and proliferation rates. At PreventionGenetics, we have observed this variant in the homozygous state in five unrelated individuals with neurodevelopmental phenotypes. In unaffected siblings in two families, the variant was absent or the present in the heterozygous state. Taken together, we interpret this variant as likely pathogenic.