Submissions for variant NM_152906.7(TANGO2):c.711-3C>G

gnomAD frequency: 0.00001  dbSNP: rs367912276

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498948	SCV000589903	likely pathogenic	not provided	2016-07-27	criteria provided, single submitter	clinical testing	The c.711-3C>G variant in the TANGO2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 8. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.711-3C>G variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.711-3C>G as a likely pathogenic variant.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001764479	SCV001999877	likely pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2021-05-21	criteria provided, single submitter	curation	The c.711-3C>G variant in TANGO2 has been reported in 5 European individuals with metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) (PMID: 30245509, 31276219) and has been identified in in 0.004% (5/113352) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs367912276). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 432207) and has been interpreted as likely pathogenic by GeneDx. Of the 5 affected individuals, 3 siblings were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the c.711-3C>G variant is pathogenic (VariationID: 224770; PMID: 30245509). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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: PM2_supporting, PP1_moderate, PM3, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498948	SCV002258743	pathogenic	not provided	2024-09-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the TANGO2 gene. It does not directly change the encoded amino acid sequence of the TANGO2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs367912276, gnomAD 0.004%). This variant has been observed in individual(s) with TANGO2-related conditions (PMID: 30245509, 31276219). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 432207). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
OMIM	RCV001764479	SCV003841009	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2023-01-27	no assertion criteria provided	literature only