chr19-1397363-C-G

Position:

chr19-1397363-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. BP4PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.707G>C (p.Gly236Ala) variant in GAMT is a missense variant predicted to cause substitution of glycine by alanine at amino acid 236 (p.Gly236Ala). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00015 (19/126040 alleles) in the European non-Finnish 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 0.323 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 the published literature. This variant is noted in ClinVar (ID 205596). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.00): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314836/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

GAMT
ENST00000252288.8 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:6B:1

Conservation

PhyloP100: 1.38

Variant links:

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 links:

GAMT (HGNC:):

GAMT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.707G>C	p.Gly236Ala	missense_variant	6/6	ENST00000252288.8	NP_000147.1	Q14353-1V9HWB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GAMT	ENST00000252288.8 linkuse as main transcript	c.707G>C	p.Gly236Ala	missense_variant	6/6	1	NM_000156.6	ENSP00000252288.1	Q14353-1
GAMT	ENST00000640762.1 linkuse as main transcript	c.638G>C	p.Gly213Ala	missense_variant	6/6	5		ENSP00000492031.1	A0A1W2PR36
GAMT	ENST00000640164.1 linkuse as main transcript	n.*20G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000859

AC:

AN:

244584

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

133064

show subpopulations

Gnomad AFR exome

AF:

0.000192

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000163

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000136

AC:

199

AN:

1458868

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

725754

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000169

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000182

Hom.:

Bravo

AF:

0.000159

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000992

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000298

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase

Uncertain:3

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. -
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.707G>C (p.Gly236Ala) variant in GAMT is a missense variant predicted to cause substitution of glycine by alanine at amino acid 236 (p.Gly236Ala). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00015 (19/126040 alleles) in the European non-Finnish 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 0.323 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 the published literature. This variant is noted in ClinVar (ID 205596). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.00): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 01, 2017	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2016

The p.G236A variant (also known as c.707G>C), located in coding exon 6 of the GAMT gene, results from a G to C substitution at nucleotide position 707. The glycine at codon 236 is replaced by alanine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs201029006. Based on data from the 1000 Genomes Project, the C allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.59% (1/170) British alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele has an overall frequency of approximately 0.02% (2/12994) total alleles studied and 0.02% (2/8594) European American alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Cerebral creatine deficiency syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 236 of the GAMT protein (p.Gly236Ala). This variant is present in population databases (rs201029006, gnomAD 0.02%). 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: 205596). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GAMT protein function. 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

0.086

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.35

CADD

Benign

4.8

DANN

Benign

0.73

DEOGEN2

Benign

0.26

T;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.50

T;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.059

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-1.2

N;.

MutationTaster

Benign

1.0

PROVEAN

Benign

0.19

N;.

REVEL

Uncertain

0.32

Sift

Benign

0.32

T;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.0

B;.

Vest4

0.13

MVP

0.29

ClinPred

0.017

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over