ClinVar Genomic variation as it relates to human health

The NM_005629.4:c.1222_1224del variant in SLC6A8 is predicted to cause a change in the length of the protein (p.Phe408del)) due to an in-frame deletion of 1 amino acid in a non-repeat region (PM4). This variant is one of the most common variants in SLC6A8 identiified in individuals with Creatine transporter deficiency. It has been reported in at least 10 individuals with clinical symptoms consistent with creatine transporter deficiency and elevated urine creatine/creatinine ratio from various countires including Italy, Spain, China, India, and Turkey (PMIDs: 12210795, 16169544, 21140503, 22551696, 23644449, 23660394, 29396939, 33656256, 34974949) (PS4_Very Strong). One male patient had clinical features consistent with creatine transporter deficiency, marked reduction of brain creatine peak on MRS. elevated urine creatine/creatinine ratio, and undetectable creatine uptake in fibroblasts with 25 μmol/L creatine (PMID: 16601898) (PP4_Strong). In gnomAD v2.1.1, the highest population minor allele frequency is 0.00009370 (1/10672 alleles) in the European non-Finnish population which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002). This is the only allele reported in any population in gnomAD v2.1.1. and there are 0 homozygotes and 0 hemizygotes (PM2_Supporting). The variant was introduced into SLC6A8 cDNA by site-directed mutagenesis and expressed in Xenopus oocytes. Creatine transport was measured in the presence of 20uM creatine and was "severely impaired" (PMID: 22644605) (PS3_Supporting). Mutation Taster predicts that the variant is "disease-causing". In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM4, PS4_VeryStrong, PP4_Strong,, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP, August 22, 2023)

Published functional studies indicate the variant impairs creatine uptake and did not generate any current in the presence of creatine, indicating that the electrogenic property and/or transport property was lost (Valayannopoulos et al., 2013); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; This variant is associated with the following publications: (PMID: 15154114, 34050321, 21140503, 24962355, 12210795, 12536364, 17825809, 27408820, 16601898, 23644449, 22551696, 19955008, 29396939, 28191890, 34426522, 33656256, 33726816, 31440721, 34974949, 22644605)

Variant summary: SLC6A8 c.1222_1224delTTC (p.Phe408del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant was absent in 133527 control chromosomes (gnomAD). c.1222_1224delTTC has been reported in the literature in multiple individuals affected with Creatine Deficiency, X-Linked (Alcaide_2011, van der Kamp_2013, Valayannopoulos_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant causes a loss of electrogenic and creatine transport activities in X. laevis oocytes (Valayannopoulos_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23644449, 21140503, 22644605). Four submitters, including a ClinGen expert panel, have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant, c.1222_1224del, results in the deletion of 1 amino acid(s) of the SLC6A8 protein (p.Phe408del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs80338740, gnomAD 0.01%). This variant has been observed in individual(s) with laboratory findings that are highly specific for X-linked creatine deficiency syndrome (PMID: 12210795, 16601898, 19706062, 21140503, 23644449, 23660394). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11698). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC6A8 function (PMID: 22644605). For these reasons, this variant has been classified as Pathogenic.

The p.Phe408del variant in SLC6A8 has been reported in the hemizygous state in at least 9 males with creatine transporter deficiency, including one de novo occurrence (Bizzi 2002 PMID: 12210795, Poo-Arguelles 2006 PMID: 16601898, Fons 2009 PMID: 19706062, Alcaide 2011 PMID: 21140503, Valayannopoulos 2012 PMID: 21660517, van de Kamp 2013 PMID: 23644449, Comeaux 2013 PMID: 23660394, Valayannopoulos 2013 PMID: 22644605). It has also been identified in 0.002% (1/53102) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant causes an in-frame deletion of the phenylalanine residue at position 408. In vitro functional studies support that this variant results in decreased creatine uptake (Poo-Arguelles 2006 PMID: 16601898, Fons 2009 PMID: 19706062). Furthermore, this variant was classified as Pathogenic on August 22, 2023 by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Variation ID 11698). In summary, this variant meets criteria to be classified as pathogenic for X-linked creatine transporter deficiency. ACMG/AMP Criteria applied: PS4, PM6, PM2_Supporting, PM4_Supporting, PS3_Supporting, PP4.

Variant interpreted as Pathogenic and reported on 03-06-2023 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

Variant interpreted as Pathogenic and reported on 01-00-1900 by GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant.