Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000156.6(GAMT):c.581T>C (p.Val194Ala)

CA314855

205606 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 06cf0406-fa6d-4cb2-88a9-244a96a94089

Approved on: 2023-01-30

Published on: 2023-03-09

HGVS expressions

NM_000156.6:c.581T>C

NM_000156.6(GAMT):c.581T>C (p.Val194Ala)

NC_000019.10:g.1397489A>G

CM000681.2:g.1397489A>G

NC_000019.9:g.1397488A>G

CM000681.1:g.1397488A>G

NC_000019.8:g.1348488A>G

NG_008283.1:g.18606A>G

NG_009785.1:g.9065T>C

ENST00000252288.8:c.581T>C

ENST00000640164.1:n.414T>C

ENST00000640762.1:c.512T>C

ENST00000252288.6:c.581T>C

NM_000156.5:c.581T>C

Benign

BP4 BA1

PP3 PM2 BS1

Evidence Links 0

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GAMT Version 1.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6(GAMT):c.581T>C variant in GAMT is a missense variant predicted to cause substitution of valine by alanine at amino acid 194 (p.Val194Ala). Population allele frequency of this variant is higher than 0.3% in two populations in gnomAD v2.1.1 (BA1 met). In silico predictors predict no damaging effect (REVEL<0.5) and no effect on splicing (SpliceAI<0.05; varSEAK - class 1). To our knowledge, this variant has not been reported in the literature in any individuals with GAMT deficiency. In summary, this variant meets the criteria to be classified as Benign 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 1.0): BA1, BP4.

BP4

BP4 (missense)(met): The computational predictor REVEL gives a score of 0.496 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). BP4 (splice)(met): The computational splicing predictor SpliceAI gives a score of 0.01 and 0.04 for acceptor loss and acceptor gain, respectively. SpliceAI gives a score of 0.00 for both donor loss and donor gain. VarSEAK predicted class 1. All of the above suggest that the variant has no impact on splicing (BP4).

BA1

The highest population minor allele frequency in gnomAD v2.1.1 is 0.001684 (21/7126 alleles) in Other population, as well as 0.003027 in the Latino/Admixed American population (107/35350 alleles), both of which are higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1).

PP3

The computational predictor REVEL gives a score of 0.496 which is below the threshold of 0.75.

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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