ClinVar Genomic variation as it relates to human health

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 95432). This premature translational stop signal has been observed in individual(s) with intellectual disability and autism (PMID: 23806237). This variant is present in population databases (rs200667343, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Ser331*) in the TUSC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TUSC3 are known to be pathogenic (PMID: 18455129, 25626710).

The c.992C>A (p.S331*) alteration, located in exon 9 (coding exon 9) of the TUSC3 gene, consists of a C to A substitution at nucleotide position 992. This changes the amino acid from a serine (S) to a stop codon at amino acid position 331. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.009% (25/282626) total alleles studied. The highest observed frequency was 0.032% (8/25094) of European (Finnish) alleles. This variant was identified in the homozygous state in an individual with intellectual disability (ID), attention deficit hyperactivity disorder, microcephaly, hypotonia, and skeletal abnormalities (Sabo, 2020). It was also identified in the compound heterozygous state with a whole gene deletion in an individual with ID and autism (Jones, 2013). Based on the available evidence, this alteration is classified as pathogenic.

The c.992C>A (p.Ser331Ter) variant in TUSC3 gene is predicted to introduce a premature translation termination codon. It is predicted to cause loss of normal protein function either through abnormal, prematurely truncated protein, or by absence of protein product due to nonsense-mediated mRNA decay. This variant has been observed at an ultra-low frequency in the general population (gnomAD database 25/282,626). This variant has been reported previously in the hemizygous state in an individual with intellectual disability and autism where it was in trans with a TUSC3 gene deletion (PMID 23806237). Biallelic loss-of-function variants in TUSC3 gene have been reported to cause autosomal recessive intellectual disability in multiple studies (PMID: 27148795, 18452889, 18455129). This variant was identified in an adult undergoing exome sequencing due to a history of intellectual disability and developmental delay. For these reasons, this variant has been classified as Pathogenic.

In the patient the TUSC3 gene contained the two variants c.992C>A and c.420dup in the compound heterozygous state. The variant c.992C>A leads to a premature stop codon, which probably causes a premature termination of protein biosynthesis at amino acid position 331. This variant is also detectable in the patient's father and is therefore paternally inherited. TUSC3 (OMIM #601385) encodes a protein involved in N-glycosylation and the magnesium transport system of the plasma membrane (PMID: 18452889, 19717468). Pathogenic homozygous nonsense variants in the TUSC3 gene have already been described in connection with the TUSC3-associated autosomal recessive mental retardation syndrome. Affected individuals show a non-syndromal global developmental delay and mild to severe mental retardation (MIM: 611093; PMID: 18452889, 27148795, 21739581). The paternally inherited variant c.992C>A p.(Ser331*) found in the patient is listed in the databases HGMD and ClinVar and described and published as pathogenic (HGMD: CM137875; ClinVar ID: 95432; PMID: 23806237). According to the current state of knowledge, the change presented here is a pathogenic variant (class 5).

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.

Criteria applied: PVS1,PM3_STR,PM2_SUP

Variant summary: TUSC3 c.992C>A (p.Ser331X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, although it is not expected to result in nonsense mediated decay. A variant downstream of this position (p.Ser343Thr) has been classified as pathogenic by ClinVar submitters with clinical evidence. The variant allele was found at a frequency of 8.4e-05 in 251246 control chromosomes (gnomAD). c.992C>A has been reported in the literature in individuals affected with Intellectual Disability (Jones_2013, Sabo_2020), and one was reported as compound heterozygous with a whole gene deletion. These data indicate that the variant is likely associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23806237, 32767738). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=5), likely pathogenic (n=1), or uncertain significance (n=1). Based on the evidence outlined above, the variant was 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 7 (MIM#611093). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (25 heterozygotes, 0 homozygotes). (SP) 0600 - Variant affects part of the annotated OST3/OST6 family, transporter family domain (DECIPHER). (I) 0710 - Another protein truncating variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. A single downstream truncating variant has been reported as a VUS (ClinVar). Additionally, a downstream missense variant, p.(Ser343Thr), has been described twice as pathogenic, and observed in at least two affected individuals (ClinVar, PMID: 26077850, PMID: 34646667). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and described in both homozygous and compound heterozygous individuals with intellectual disability, developmental delay and/or autism (ClinVar, PMID: 32767738). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign