Submissions for variant NM_005629.4(SLC6A8):c.912G>C (p.Gln304His)

dbSNP: rs1064794836

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV003333989	SCV004042600	uncertain significance	Creatine transporter deficiency	2023-08-24	reviewed by expert panel	curation	The NM_005629.4:c.912G>C in SLC6A8 is a missense variant predicted to cause substitution of glutamine by histidine at amino acid 304 (p.Gln304His). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.749 (>0.75 provides evidence that correlates with impact to SLC6A8 function). The computational splicing predictors SpliceAI and varSEAK predict that the variant may disrupt the donor splice site of intron 5 (PP3). Another variant at this position, c.912G>A (p.Gln304=), which has been reported in a patient with creatine transporter deficiency and may disrupt normal splicing of SLC6A8 (PMIDs: 17101918, 23660394, 29478817) has been classified as likely pathogenic by the ClinGen CCDS VCEP. Comparison of the in silico predictions for c.912G>A (p.Gln304=) and c.912G>C (p.Gln304His) suggest that c.912G>A (p.Gln304=) is less damaging to splicing than c.912G>C (p.Gln304His) (PS1_Supporting). To our knowledge, c.912G>C (p.Gln304His) has not been reported in the literature and results of functional and splicing studies are unavailable. However, there is a ClinVar entry for this variant (Variation ID: 420991); follow up with the lab did not provide sufficient evidence to apply additional criteria. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PP3, PM2_Supporting, PS1_Supporting. (Classification approved by the ClinGen CCDS VCEP, Jan 12, 2023)
GeneDx	RCV000483324	SCV000570051	likely pathogenic	not provided	2016-04-19	criteria provided, single submitter	clinical testing	The Q304H variant in the SLC6A8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Q304H 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. The Q304H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a nucleotide and amino acid position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that c.912 G>C (aka Q304H) might damage the natural splice donor site for exon 5, which may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of c.912 G>C is unknown. A splicing variant at this same nucleotide position (c.912 G>A) has been reported previously in a male patient with creatine transporter deficiency (Lion-Francois et al., 2006). Therefore, the Q304H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.