Submissions for variant NM_005629.4(SLC6A8):c.611_612delinsAC (p.Ala204Asp)

dbSNP: rs1569539288

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV002067020	SCV005619912	uncertain significance	Creatine transporter deficiency	2024-11-08	reviewed by expert panel	curation	The NM_005629.4:c.611_612delinsAC variant in SLC6A8 is a multi-nucleotide variant that replaces CT with AC, resulting in the substitution of an alanine by an aspartate at amino acid position 204 (p.Ala204Asp). 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 0.0001094 (3/27411 alleles) in the Admixed American population, 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. Of the 3 total alleles in gnomAD v2.1.1, there is one hemizygote reported, which is less than the ClinGen CCDS VCEP’s threshold for BS2 (≥2 hemizygotes), such that BS2 is not met. The computational predictor REVEL gives a score of 0.148 for the Ala204Asp substitution (BP4). There is a ClinVar entry for this variant (Variation ID: 588254, one-star review status), with conflicting interpretations of pathogenicity (two submitters: 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): BP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024)
Ambry Genetics	RCV002316171	SCV000847801	uncertain significance	Inborn genetic diseases	2016-09-08	criteria provided, single submitter	clinical testing	The c.611_612delCTinsAC variant (also known as p.A204D), located in coding exon 3 of the SLC6A8 gene, results from a deletion of CT and insertion of AC at nucleotide positions 611 to 612. This results in the substitution of the alanine residue for an aspartic acid residue at codon 204, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples with coverage at this position. This amino acid position is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002067020	SCV002442478	likely benign	Creatine transporter deficiency	2025-01-30	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV002507256	SCV002817226	uncertain significance	not provided	2020-06-05	criteria provided, single submitter	clinical testing	This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586899	SCV005076862	uncertain significance	not specified	2024-04-09	criteria provided, single submitter	clinical testing	Variant summary: SLC6A8 c.611_612delinsAC (p.Ala204Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 182960 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.611_612delinsAC has been reported in the literature in a hemizygous infant undergoing neonatal screening for a suspected genetic disorder (Maron_2023). This report does not provide unequivocal conclusions about association of the variant with Creatine Deficiency, X-Linked. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37432431). ClinVar contains an entry for this variant (Variation ID: 588254). Based on the evidence outlined above, the variant was classified as uncertain significance.