ClinVar Genomic variation as it relates to human health

Pathogenicity based on finding it once homozygous in a 1-year-old male with episodic metabolic crises, developmental delay, hypotonia

The c.605+1G>A variant is a canonical splice site variant that is predicted to result in aberrant splicing. It has been previously reported in the homozygous state in a patient with MECRCN (PMID: 26805781). This variant has been reported in one Latino and five South Asian individuals in the ExAC database, with an overall allele frequency of 0.0003192. Thus it is presumed to be rare. This genomic position is well conserved. Based on the combined evidence, the c.605+1G>A variant is classified as pathogenic.

The c.605+1G>A variant in TANGO2 has been reported in 2 individuals with metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) (PMID: 26805781, 29891059) and has been identified in in 0.04% (8/22394) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs372949028). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of the 2 affected individuals, 1 of those was a homozygote, and one was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the c.605+1G>A variant is pathogenic (Variation ID: 208823; PMID: 26805781, 29891059). This variant has also been reported in ClinVar (Variation ID#: 208824) and has been interpreted as likely pathogenic/pathogenic by Kariminejad - Najmabadi Pathology & Genetics Center, Baylor Genetics, Rady Children's Institute for Genomic Medicine (Rady Children's Hospital San Diego), OMIM, and GeneReviews. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the TANGO2 gene is a strongly established disease mechanism in autosomal recessive MECRCN. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive MECRCN. ACMG/AMP Criteria applied: PVS1_strong, PM3 (Richards 2015).

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30650451, 31980526, 26805781)

This sequence change affects a donor splice site in intron 7 of the TANGO2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TANGO2 are known to be pathogenic (PMID: 26805781, 26805782). This variant is present in population databases (rs372949028, gnomAD 0.04%). Disruption of this splice site has been observed in individuals with clinical features of TANGO2-related conditions (PMID: 26805781, 30650451; Invitae). ClinVar contains an entry for this variant (Variation ID: 208824). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The TANGO2 c.605+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in multiple individuals with autosomal recessive TANGO2 deficiency disorder (see for example, Lalani et al. 2016. PubMed ID: 26805781; Miyake et al. 2022. PubMed ID: 36473599; Dias et al. 2023. PubMed ID: 37562170). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD. Variants that disrupt the consensus splice donor site in TANGO2 are expected to be pathogenic. This variant is interpreted as pathogenic.