Submissions for variant NM_006517.5(SLC16A2):c.940C>T (p.Arg314Ter)

dbSNP: rs766773277

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193469	SCV000248889	pathogenic	Allan-Herndon-Dudley syndrome	2014-06-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000760473	SCV000890362	pathogenic	not provided	2016-01-04	criteria provided, single submitter	clinical testing	The R314X variant in the SLC16A2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R314X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Protein truncating pathogenic variants downstream of this variant have been reported in the Human Gene Mutation Database in association with Allan-Herndon-Dudley syndrome (Stenson et al., 2014), supporting the pathogenicity of more upstream truncating variants. We interpret R314X as a pathogenic variant.
3billion, Medical Genetics	RCV000193469	SCV002012274	pathogenic	Allan-Herndon-Dudley syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as pathogenic (ClinVar ID: VCV000212186.1). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853109	SCV002225401	pathogenic	Spastic paraplegia	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg314*) in the SLC16A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC16A2 are known to be pathogenic (PMID: 20083155, 25527620). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with MCT8 deficiency (PMID: 32559475). This variant is also known as p.R388X. ClinVar contains an entry for this variant (Variation ID: 212186). 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.