ClinVar Miner

Submissions for variant NM_005629.4(SLC6A8):c.70G>C (p.Ala24Pro)

gnomAD frequency: 0.00002  dbSNP: rs1557043775
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen RCV000555105 SCV002600196 uncertain significance Creatine transporter deficiency 2022-06-06 reviewed by expert panel curation The NM_005629.4(SLC6A8):c.70G>C (p.Ala24Pro) variant in SLC6A8 is a missense variant predicted to cause substitution of Alanine for Proline at amino acid 24 (p.Ala24Pro). In gnomAD v2.1.1, the highest population minor allele frequency is 0.0000159 (1/62731 alleles) in the European population, with no hemi- or homozygotes, which is <0.0002 therefore PM2_Supporting criteria applicable. The computational predictor REVEL gives a score of 0.085 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function (BP4). To our knowledge, this variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID: 465148). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
Invitae RCV000555105 SCV000640034 uncertain significance Creatine transporter deficiency 2022-07-01 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 24 of the SLC6A8 protein (p.Ala24Pro). This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SLC6A8-related conditions. ClinVar contains an entry for this variant (Variation ID: 465148). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC6A8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc. RCV001829583 SCV002084544 uncertain significance Creatine deficiency syndrome 1 2019-11-11 no assertion criteria provided clinical testing

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