rs778279369

Positions:

• chr19-1397448-G-A
• chr19-1397448-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. BP4 PM5_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.622C>T variant in GAMT is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 208 (p.Arg208Cys). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00016 (3/18330 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). The computational predictor REVEL gives a score of 0.1309 which is below the threshold of 0.5, evidence that correlates with no impact to GAMT function (BP4). Two additional missense variants at this amino acid position have been reported; c.623G>A (p.Arg208His) (ClinVarID: 577478) and c.623G>C (p.Arg208Pro) (PMID 24415674). The ClinGen CCDS VCEP has classified p.Arg208Pro as likely pathogenic, while p.Arg208His has been classified as a VUS (PM5_Supporting). To our knowledge, c.622C>T (p.Arg208Pro) has not been previously reported in the published literature, but has been noted in ClinVar (Variation ID: 544261). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0: PM2_Supporting, PM5_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA9043556/MONDO:0012999/026

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 0.436

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 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.622C>T	p.Arg208Cys	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.622C>T	p.Arg208Cys	missense_variant	6/6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000640762.1	c.553C>T	p.Arg185Cys	missense_variant	6/6	5		ENSP00000492031.1
GAMT	ENST00000640164.1	n.455C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000283 AC: 7 AN: 247330 Hom.: 0 AF XY: 0.0000372 AC XY: 5 AN XY: 134300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1457980 Hom.: 0 Cov.: 31 AF XY: 0.0000221 AC XY: 16 AN XY: 725404

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Uncertain:3

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.622C>T variant in GAMT is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 208 (p.Arg208Cys). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00016 (3/18330 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). The computational predictor REVEL gives a score of 0.1309 which is below the threshold of 0.5, evidence that correlates with no impact to GAMT function (BP4). Two additional missense variants at this amino acid position have been reported; c.623G>A (p.Arg208His) (ClinVarID: 577478) and c.623G>C (p.Arg208Pro) (PMID 24415674). The ClinGen CCDS VCEP has classified p.Arg208Pro as likely pathogenic, while p.Arg208His has been classified as a VUS (PM5_Supporting). To our knowledge, c.622C>T (p.Arg208Pro) has not been previously reported in the published literature, but has been noted in ClinVar (Variation ID: 544261). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0: PM2_Supporting, PM5_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cerebral creatine deficiency syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 208 of the GAMT protein (p.Arg208Cys). This variant is present in population databases (rs778279369, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 544261). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Uncertain	0.49	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.59	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.97	L;.
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.13
Sift	Benign	0.10	T;.
Sift4G	Uncertain	0.045	D;.
Polyphen		0.0060	B;.
Vest4		0.062
MutPred		0.42		Loss of disorder (P = 0.1136);.;
MVP		0.61
ClinPred		0.022	T
GERP RS		0.17
Varity_R		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778279369; hg19: chr19-1397447;