Submissions for variant NM_005629.4(SLC6A8):c.833G>A (p.Arg278His)

gnomAD frequency: 0.00002  dbSNP: rs782802482

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001873645	SCV005619909	uncertain significance	Creatine transporter deficiency	2024-11-08	reviewed by expert panel	curation	The NM_005629.4:c.833G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of an arginine by a histidine at amino acid position 278 (p.Arg278His). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00007 (2/27341 alleles) in the Latino population and 1 hemizygote across all populations, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.353, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 917570, one-star review status), with conflicting interpretations of pathogenicity (one submitter: uncertain significance; one submitter: likely benign). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): no criteria met. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174606	SCV001337800	uncertain significance	not specified	2020-01-21	criteria provided, single submitter	clinical testing	Variant summary: SLC6A8 c.833G>A (p.Arg278His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 181833 control chromosomes in the gnomAD database, including 1 hemizygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.833G>A in individuals affected with Creatine deficiency, X-linked and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873645	SCV002317966	likely benign	Creatine transporter deficiency	2023-10-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001828584	SCV002084558	uncertain significance	Creatine deficiency syndrome 1	2020-02-21	no assertion criteria provided	clinical testing