ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.225G>A (p.Ala75=)

gnomAD frequency: 0.00002  dbSNP: rs202151546
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Total submissions: 5
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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 RCV001127425 SCV003852707 likely benign Deficiency of guanidinoacetate methyltransferase 2023-03-09 reviewed by expert panel curation The NM_000156.6(GAMT):c.225G>A (p.Ala75=) variant is a synonymous variant for which splicing prediction algorithms (SpliceAI, varSEAK) predict no impact to the splice consensus sequence nor the creation of a new splice site (BP4); however, the residue altered (Ala75) is conserved through zebrafish. Thus, BP7 is not met. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00117 (21/17954 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.001), and therefore meets this criterion (BS1). There is a ClinVar entry for this variant (Variation ID: 137433). In summary, this variant meets the crietria to be classified as likely benign for GAMT deficiency. GAMT-specific criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (CCDS VCEP): BS1, BP4. (Classification approved by the ClinGen CCDS VCEP on March 9, 2023).
GeneDx RCV000125189 SCV000168630 benign not specified 2014-05-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV000862748 SCV001003296 likely benign Cerebral creatine deficiency syndrome 2024-06-09 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001127425 SCV001286737 uncertain significance Deficiency of guanidinoacetate methyltransferase 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics RCV002444588 SCV002733368 likely benign Inborn genetic diseases 2019-03-18 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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