19-1397447-C-T

Position:

chr19-1397447-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5_SupportingPM2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.623G>A variant in GAMT is a missense variant predicted to cause substitution of arginine by histidine at amino acid 208 (p.Arg208His). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 (3/24752 alleles) in the African 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 0.279 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.622C>T (p.Arg208Cys) (ClinVarID: 5442618) and c.623G>C (p.Arg208Pro) (PMID 24415674). The ClinGen CCDS VCEP has classified p.Arg208Pro as likely pathogenic, while p.Arg208Cys has been classified as a VUS (PM5_Supporting). To our knowledge, c.623G>A (p.Arg208His) has not been previously reported in the published literature, but has been noted in ClinVar (ClinVar ID 577478). 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/CA9043553/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4

Conservation

PhyloP100: 0.126

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

PM5

BP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAMT	NM_000156.6 linkuse as main transcript	c.623G>A	p.Arg208His	missense_variant	6/6	ENST00000252288.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8 linkuse as main transcript	c.623G>A	p.Arg208His	missense_variant	6/6	1	NM_000156.6	P1	Q14353-1
GAMT	ENST00000640762.1 linkuse as main transcript	c.554G>A	p.Arg185His	missense_variant	6/6	5
GAMT	ENST00000640164.1 linkuse as main transcript	n.456G>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000364

AC:

AN:

247300

Hom.:

AF XY:

0.0000372

AC XY:

AN XY:

134304

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000261

AC:

AN:

1457948

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

725392

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase

Uncertain:2

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.623G>A variant in GAMT is a missense variant predicted to cause substitution of arginine by histidine at amino acid 208 (p.Arg208His). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 (3/24752 alleles) in the African 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 0.279 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.622C>T (p.Arg208Cys) (ClinVarID: 5442618) and c.623G>C (p.Arg208Pro) (PMID 24415674). The ClinGen CCDS VCEP has classified p.Arg208Pro as likely pathogenic, while p.Arg208Cys has been classified as a VUS (PM5_Supporting). To our knowledge, c.623G>A (p.Arg208His) has not been previously reported in the published literature, but has been noted in ClinVar (ClinVar ID 577478). 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	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2017

The p.R208H variant (also known as c.623G>A), located in coding exon 6 of the GAMT gene, results from a G to A substitution at nucleotide position 623. The arginine at codon 208 is replaced by histidine, an amino acid with highly similar properties. 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 alteration remains unclear. -

Cerebral creatine deficiency syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 208 of the GAMT protein (p.Arg208His). This variant is present in population databases (rs767887772, 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: 577478). 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

0.065

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.24

DANN

Benign

0.97

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.50

T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.77

N;.

MutationTaster

Benign

1.0

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.28

Sift

Benign

0.11

T;.

Sift4G

Uncertain

0.038

D;.

Polyphen

0.0030

B;.

Vest4

0.041

MutPred

0.34

Gain of sheet (P = 0.0477);.;

MVP

0.49

ClinPred

0.020

GERP RS

-5.0

Varity_R

0.11

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