chr19-1397393-G-A

Position:

• chr19-1397393-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. BP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6: c.677C>T variant in GAMT is a missense variant predicted to result in the substitution of proline for leucine at amino acid 226 (p.Pro226Leu). It is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.292 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). To our knowledge, this variant has not been reported in published literature in individuals with GAMT deficiency, and the results of functional studies are unavailable. This variant has been previously reported in ClinVar (Variation ID: 205594). In summary, this variant meets the criteria to be classified as a variant of uncertain significancefor GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314832/MONDO:0012999/026

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GAMT ENST00000252288.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 0.648

Genes affected

GAMT (HGNC:4136): (guanidinoacetate N-methyltransferase) The protein encoded by this gene is a methyltransferase that converts guanidoacetate to creatine, using S-adenosylmethionine as the methyl donor. Defects in this gene have been implicated in neurologic syndromes and muscular hypotonia, probably due to creatine deficiency and accumulation of guanidinoacetate in the brain of affected individuals. Two transcript variants encoding different isoforms have been described for this gene. Pseudogenes of this gene are found on chromosomes 2 and 13. [provided by RefSeq, Feb 2012]

GAMT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6	c.677C>T	p.Pro226Leu	missense_variant	6/6	ENST00000252288.8	NP_000147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.677C>T	p.Pro226Leu	missense_variant	6/6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000640762.1	c.608C>T	p.Pro203Leu	missense_variant	6/6	5		ENSP00000492031.1
GAMT	ENST00000640164.1	n.510C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460216 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726426

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2012

p.Pro226Leu (CCA>CTA): c.677 C>T in exon 6 of the GAMT gene (NM_000156.4) The Pro226Leu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Pro226Leu in approximately 5,000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Although both Proline and Leucine are uncharged, non-polar amino acids, the loss of a bulky Proline residue may alter the secondary structure of the protein. However, Pro226Leu alters a position that is not highly conserved in the GAMT protein or in related proteins. Several in silico models predict that Pro226Leu may be benign, while another suggests this variant may be damaging to protein structure/function. Therefore, based on the currently available information, it is unclear whether Pro226Leu is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -

Deficiency of guanidinoacetate methyltransferase Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Jun 06, 2022

The NM_000156.6: c.677C>T variant in GAMT is a missense variant predicted to result in the substitution of proline for leucine at amino acid 226 (p.Pro226Leu). It is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.292 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). To our knowledge, this variant has not been reported in published literature in individuals with GAMT deficiency, and the results of functional studies are unavailable. This variant has been previously reported in ClinVar (Variation ID: 205594). In summary, this variant meets the criteria to be classified as a variant of uncertain significancefor GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.82	D
PROVEAN	Uncertain	-3.7	D;.
REVEL	Uncertain	0.29
Sift	Benign	0.034	D;.
Sift4G	Uncertain	0.028	D;.
Polyphen		0.56	P;.
Vest4		0.18
MutPred		0.51		Gain of helix (P = 0.062);.;
MVP		0.89
ClinPred		0.74	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs796052528; hg19: chr19-1397392;