ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.438A>G (p.Thr146=)

gnomAD frequency: 0.00001  dbSNP: rs80338733
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen RCV000020142 SCV002600157 uncertain significance Deficiency of guanidinoacetate methyltransferase 2022-06-06 reviewed by expert panel curation The NM_000156.6:c.438A>G (p.Thr146=) variant in GAMT is a synonymous variant in exon 4 that is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). This variant has been previously reported in an individual with GAMT deficiency who had significantly decreased creatine peak on MRS (PMID: 7808840) and GAMT activity <0.1% versus normal in fibroblasts (PMID: 11978605) (PP4_Strong). Familial analysis showed that this individual harbored the variant in cis with c.299_311dup (also known as c.309ins13; pathogenic based on classification by the ClinGen CCDS VCEP) and had co-inherited the variants from his unaffected mother (BP2); he was also heterozygous for the pathogenic variant c.327G>A, inherited from his father. Of note, his unaffected brother also harbored the two maternally co-inherited (c.438A>G and c.309ins13) variants. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 (4/ 113532 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). It is noted in ClinVar (ID 21066). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT 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): PP4_Strong, PM2_Supporting, BP2, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
Baylor Genetics RCV000020142 SCV001530156 uncertain significance Deficiency of guanidinoacetate methyltransferase 2018-08-14 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp RCV002054453 SCV002479902 likely benign Cerebral creatine deficiency syndrome 2023-09-20 criteria provided, single submitter clinical testing
GeneReviews RCV000020142 SCV000040468 not provided Deficiency of guanidinoacetate methyltransferase no assertion provided literature only

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