Variant: NM_000156.6(GAMT):c.403G>A (p.Asp135Asn)

CA9043671

573140 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 8a818f12-30b9-40f0-9411-9be1e355f21b

Approved on: 2023-06-08

Published on: 2023-06-08

HGVS expressions

NM_000156.6:c.403G>A
NM_000156.6(GAMT):c.403G>A (p.Asp135Asn)
NC_000019.10:g.1399184C>T
CM000681.2:g.1399184C>T
NC_000019.9:g.1399183C>T
CM000681.1:g.1399183C>T
NC_000019.8:g.1350183C>T
NG_009785.1:g.7370G>A
ENST00000252288.8:c.403G>A
ENST00000447102.8:c.403G>A
ENST00000591788.3:n.86G>A
ENST00000640164.1:n.236G>A
ENST00000640762.1:c.334G>A
ENST00000252288.6:c.403G>A
ENST00000447102.7:c.403G>A
ENST00000591788.2:n.88G>A
NM_000156.5:c.403G>A
NM_138924.2:c.403G>A
NM_138924.3:c.403G>A

Pathogenic

• Met criteria codes: PM2_Supporting PP4_Strong PM5_Supporting PS3_Supporting PM3 PP3

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

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6(GAMT):c.403G>A variant in GAMT is predicted to result in the substitution of aspartate by asparagine at amino acid 135 (p.Asp135Asn). Four probands and one affected sibling have been reported with this variant, all with clinical symptoms consistent with GAMT deficiency, evidence of elevated guanidinoacetate and low creatine in plasma and/or urine, and reduced creatine on brain MRS with guanidinoacetate peak also noted for two patients. In addition, one proband was shown to have deficient GAMT activity in fibroblasts (PMID: 19027335, 19388150, 24071436, 24268530, 24415674) (PP4_Strong). Each of these individuals is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic or likely pathogenic by the ClinGen CCDS VCEP including c.327G>A (2 patients; PMID: 24071436, 24268530, 24415674), c.299dup13 (a.k.a. c.299_311dup) (PMID: 19388150), and c.507_521dup15 (p.Cys169_Ser173dup) (PMID: 19027335)(PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00011 (2/18390 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). When the variant was expressed in GAMT-deficient fibroblasts, GAMT enzyme activity was undetectable (PMID: 24415674). The computational predictor REVEL gives a score of 0.856 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). Another variant at the same amino acid position, c.403G>T (p.Asp135Tyr), has been classified as likely pathogenic by the ClinGen CCDS VCEP (and would be likely pathogenic even without the use of PM5, therefore avoiding circular logic) (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 573140). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0); PP4_Strong, PM3, PP3, PS3_Supporting, PM2_Supporting, PM5_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 8, 2023)

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00011 (2/18390 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).
• PP4_Strong: Four probands and one affected sibling have been reported with this variant and clincal symptoms consistent with GAMT defciiency. All reported patients had evidence of elevated guanidinoacetate and low creatine in plasma and/or urine, and reduced creatine on brain MRS with guanidinoacetate peak also noted for two patients. In addition, one proband was shown to have deficient GAMT activity in fibroblasts (PMID: 19027335, 19388150, 24071436, 24268530, 24415674 (PP4_Strong).
• PM5_Supporting: Another variant at the same amino acid position, c.403G>T (p.Asp135Tyr), has been classified as likely pathogenic by the ClinGen CCDS VCEP (and would be likely pathogenic even without the use of PM5, therefore avoiding circular logic) (PM5_Supporting).
• PS3_Supporting: When the variant was expressed in GAMT-deficient fibroblasts, GAMT enzyme activity was undetectable (PMID: 24415674).
• PM3: Four patients have been reported who are compound heterozygous, phase unknown, for the variant and another variant in GAMT that has been classified as pathogenic or likely pathogenic by the ClinGen CCDS VCEP including c.327G>A (2 patients; 2 x 0.5 points, PMID: 24071436, 24268530, 24415674), c.299dup13 (a.k.a. c.299_311dup) (0.5 points) (PMID: 19388150), and c.507_521dup15 (p.Cys169_Ser173dup) (PMID: 19027335) (0.25 points). Total 1.75 points (PM3)
• PP3: The computational predictor REVEL gives a score of 0.856 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). No impact on splicing predicted by SpliceAI.