Cerebral creatine deficiency syndromes (CCDS) are inherited metabolic phenotypes of creatine synthesis and transport. There are two enzyme deficiencies, guanidinoacetate methyltransferase (GAMT), encoded by and arginine-glycine amidinotransferase (AGAT), encoded by which are involved in the synthesis of creatine. After synthesis, creatine is taken up by a sodium-dependent membrane bound creatine transporter (CRTR), encoded by into all organs. Creatine uptake is very important especially in high energy demanding organs such as the brain, and muscle. To classify the pathogenicity of variants in and we developed the CCDS Variant Curation Expert Panel (VCEP) in 2018, supported by The Clinical Genome Resource (ClinGen), a National Institutes of Health (NIH)-funded resource. We developed disease-specific variant classification guidelines for and related CCDS adapted from the American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant interpretation guidelines. We applied specific variant classification guidelines to 30 pilot variants in each of the three genes that have variants associated with CCDS. Our CCDS VCEP was approved by the ClinGen Sequence Variant Interpretation Working Group (SVI WG) and Clinical Domain Oversight Committee in July 2022. We curated 181 variants including 72 variants in , 45 variants in , and 64 variants in and submitted these classifications to ClinVar, a public variant database supported by the National Center for Biotechnology Information. Missense variants were the most common variant type in all three genes. We submitted 32 new variants and reclassified 34 variants with conflicting interpretations. We report specific phenotype (PP4) using a points system based on the urine and plasma guanidinoacetate and creatine levels, brain magnetic resonance spectroscopy (MRS) creatine level, and enzyme activity or creatine uptake in fibroblasts ranging from PP4, PP4_Moderate and PP4_Strong. Our CCDS VCEP is one of the first panels applying disease specific variant classification algorithms for an X-linked disease. The availability of these guidelines and classifications can guide molecular genetics and genomic laboratories and health care providers to assess the molecular diagnosis of individuals with a CCDS phenotype.

中文翻译：

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ClinGen 变异管理专家小组针对脑肌酸缺乏综合征的 GAMT、GATM 和 SLC6A8 变异分类的建议

脑肌酸缺乏综合征（CCDS）是肌酸合成和转运的遗传性代谢表型。有两种酶缺乏，即胍基乙酸甲基转移酶 (GAMT)（由其编码）和精氨酸-甘氨酸脒基转移酶 (AGAT)（由其编码）参与肌酸的合成。合成后，肌酸被钠依赖性膜结合肌酸转运蛋白 (CRTR) 吸收，并编码进入所有器官。肌酸的吸收非常重要，尤其是在大脑和肌肉等高能量需求器官中。为了对变异的致病性进行分类，我们于 2018 年开发了 CCDS 变异管理专家小组 (VCEP)，并得到了美国国立卫生研究院 (NIH) 资助的资源临床基因组资源 (ClinGen) 的支持。我们根据美国医学遗传学会/分子病理学协会 (ACMG/AMP) 变异解释指南改编了疾病特异性变异分类指南和相关 CCDS。我们将特定的变异分类指南应用于具有与 CCDS 相关变异的三个基因中每一个的 30 个试点变异。我们的 CCDS VCEP 于 2022 年 7 月获得了 ClinGen 序列变异解释工作组 (SVI WG) 和临床领域监督委员会的批准。我们策划了 181 个变异，包括 中的 72 个变异、 中的 45 个变异和 中的 64 个变异，并将这些分类提交给 ClinVar，由国家生物技术信息中心支持的公共变异数据库。错义变异是所有三个基因中最常见的变异类型。我们提交了 32 个新变体，并对 34 个解释相互冲突的变体进行了重新分类。我们使用基于尿液和血浆胍基乙酸和肌酸水平、脑磁共振波谱 (MRS) 肌酸水平以及成纤维细胞中的酶活性或肌酸摄取的积分系统报告特定表型 (PP4)，范围从 PP4、PP4_中度和 PP4_强。我们的 CCDS VCEP 是首批针对 X 连锁疾病应用疾病特异性变异分类算法的面板之一。这些指南和分类的可用性可以指导分子遗传学和基因组实验室以及医疗保健提供者评估具有 CCDS 表型的个体的分子诊断。