GeneBe

rs80338740

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_005629.4(SLC6A8):​c.1222_1224delTTC​(p.Phe408del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 112,006 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

SLC6A8
NM_005629.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:7O:3

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
SLC6A8 (HGNC:11055): (solute carrier family 6 member 8) The protein encoded by this gene is a plasma membrane protein whose function is to transport creatine into and out of cells. Defects in this gene can result in X-linked creatine deficiency syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_005629.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant X-153693978-GTTC-G is Pathogenic according to our data. Variant chrX-153693978-GTTC-G is described in ClinVar as [Pathogenic]. Clinvar id is 11698.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-153693978-GTTC-G is described in Lovd as [Pathogenic]. Variant chrX-153693978-GTTC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC6A8NM_005629.4 linkuse as main transcriptc.1222_1224delTTC p.Phe408del conservative_inframe_deletion 8/13 ENST00000253122.10 NP_005620.1 P48029-1X5D9C4
SLC6A8NM_001142805.2 linkuse as main transcriptc.1192_1194delTTC p.Phe398del conservative_inframe_deletion 8/13 NP_001136277.1 P48029Q59EV7
SLC6A8NM_001142806.1 linkuse as main transcriptc.877_879delTTC p.Phe293del conservative_inframe_deletion 8/13 NP_001136278.1 P48029-4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC6A8ENST00000253122.10 linkuse as main transcriptc.1222_1224delTTC p.Phe408del conservative_inframe_deletion 8/131 NM_005629.4 ENSP00000253122.5 P48029-1

Frequencies

GnomAD3 genomes
AF:
0.00000893
AC:
1
AN:
112006
Hom.:
0
Cov.:
24
AF XY:
0.00
AC XY:
0
AN XY:
34184
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1066528
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
346804
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000893
AC:
1
AN:
112006
Hom.:
0
Cov.:
24
AF XY:
0.00
AC XY:
0
AN XY:
34184
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000660
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7Other:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Creatine transporter deficiency Pathogenic:5Other:3
Pathogenic, reviewed by expert panelcurationClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGenAug 22, 2023The 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) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 16, 2023This 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. -
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2002- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 18, 2023The 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. -
not provided, no classification providedphenotyping onlyGenomeConnect - Brain Gene Registry-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/. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 20, 2023Variant 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. -
not provided, no classification providedphenotyping onlyGenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies-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. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 05, 2023Published 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) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338740; hg19: chrX-152959433; API