Submissions for variant NM_005629.4(SLC6A8):c.318CTT[1] (p.Phe107del)

dbSNP: rs80338739

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV000020635	SCV002600174	pathogenic	Creatine transporter deficiency	2022-06-06	reviewed by expert panel	curation	The NM_005629.4(SLC6A8):c.318_320delCTT variant in SLC6A8 is a 3 nucleotide deletion predicted to lead to the in-frame deletion of a single Phenylalanine at amino acid 107 (p.Phe107del). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. Individuals with this variant have been reported in the literature. In deGrauw, 2002 [PMID:12536364] a family with two affected males, one affected female, and one asymptomatic female (mother) were reported. Individual MB from this family was reported with elevated creatine: creatinine in urine, MRS showing absent creatine and phosphocreatine peak, and is used to fulfill PP4_Strong criteria and therefore not used as PS4 evidence. Segregations from this family are used as PP1 evidence. At least 3 additional affected individuals meeting PP4 criteria have been reported [PMID:19188083, 29435807, 33267903], not including the family from deGrauw. Functional studies have been performed, but do not meet the criteria established for PS3 evidence from the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (creatine <125uM creatine used for creatine transport assay) [PMID: 17465020]. There is a ClinVar entry for this variant (Variation ID:21448). In summary, this variant meets the criteria to be classified as a Pathogenic 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): PS4, PP4_Strong, PM4, PP1_Moderate, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
GeneDx	RCV000479265	SCV000568381	pathogenic	not provided	2022-10-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect on creatine uptake (Rosenberg et al., 2007); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 1 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 29435807, 34050321, 25590979, 12889669, 12536364, 17465020)
Ambry Genetics	RCV000623073	SCV000742827	likely pathogenic	Inborn genetic diseases	2017-07-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020635	SCV002122371	pathogenic	Creatine transporter deficiency	2023-12-15	criteria provided, single submitter	clinical testing	This variant, c.321_323del, results in the deletion of 1 amino acid(s) of the SLC6A8 protein (p.Phe107del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical and/or biochemical features of creatine transporter deficiency (PMID: 12536364, 12889669, 15154114, 25590979). It has also been observed to segregate with disease in related individuals. This variant is also known as c.316_318delTTC (p.Phe106del). ClinVar contains an entry for this variant (Variation ID: 21448). 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: 17465020). For these reasons, this variant has been classified as Pathogenic.
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000020635	SCV003919049	pathogenic	Creatine transporter deficiency	2023-04-20	criteria provided, single submitter	research
Baylor Genetics	RCV000020635	SCV004202503	pathogenic	Creatine transporter deficiency	2023-04-23	criteria provided, single submitter	clinical testing
GeneReviews	RCV000020635	SCV000041155	not provided	Creatine transporter deficiency		no assertion provided	literature only
GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	RCV000020635	SCV001169655	not provided	Creatine transporter deficiency		no assertion provided	phenotyping only	Variant identified in multiple registry participants. Variant interpreted as Likely pathogenic and reported on 08-25-2017 by lab or GTR ID 61756. Variant reported on 05-01-2014 by lab or GTR ID Amsterdam UMC Metabolic Laboratory. GenomeConnect - Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.