rs201322234

Positions:

chr2-69363563-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP2PP5_Very_StrongBP4

The NM_001244710.2(GFPT1):c.331C>T(p.Arg111Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

GFPT1
NM_001244710.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.41

Variant links:

Genes affected

GFPT1 (HGNC:4241): (glutamine--fructose-6-phosphate transaminase 1) This gene encodes the first and rate-limiting enzyme of the hexosamine pathway and controls the flux of glucose into the hexosamine pathway. The product of this gene catalyzes the formation of glucosamine 6-phosphate. [provided by RefSeq, Sep 2008]

GFPT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GFPT1. . Gene score misZ 4.3482 (greater than the threshold 3.09). Trascript score misZ 4.3487 (greater than threshold 3.09). GenCC has associacion of gene with congenital myasthenic syndromes with glycosylation defect, congenital myasthenic syndrome 12.

PP5

Variant 2-69363563-G-A is Pathogenic according to our data. Variant chr2-69363563-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-69363563-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.41946968). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GFPT1	NM_001244710.2 linkuse as main transcript	c.331C>T	p.Arg111Cys	missense_variant	4/20	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4 linkuse as main transcript	c.331C>T	p.Arg111Cys	missense_variant	4/19		NP_002047.2
GFPT1	XM_017003801.2 linkuse as main transcript	c.406C>T	p.Arg136Cys	missense_variant	4/20		XP_016859290.1
GFPT1	XM_017003802.3 linkuse as main transcript	c.406C>T	p.Arg136Cys	missense_variant	4/19		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9 linkuse as main transcript	c.331C>T	p.Arg111Cys	missense_variant	4/20	5	NM_001244710.2	ENSP00000349860		Q06210-1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251416

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000296

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000765

Hom.:

Bravo

AF:

0.000291

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 12

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 02, 2018	The GFPT1 c.331C>T (p.Arg111Cys) missense variant has been reported in two studies and identified in nine individuals with congenital myasthenic syndrome, including in six homozygotes and in three compound heterozygotes, from four unrelated families (Senderek et al. 2011; Bauche et al. 2017). Segregation data from the families was consistent with autosomal recessive inheritance. The p.Arg111Cys variant was absent from at least 240 controls but is reported at a frequency of 0.000566 in the Latino population of the Genome Aggregation Database. In addition, Bauche et al. (2017) identified four unrelated affected individuals that carried a different amino acid change at the same residue (p.Arg111His) in a compound heterozygous state, suggesting that the Arg111 codon may be a mutational hot spot. Based on the evidence, the p.Arg111Cys variant is classified as likely pathogenic for congenital myasthenic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2023	For these reasons, this variant has been classified as Pathogenic. 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 GFPT1 protein function. ClinVar contains an entry for this variant (Variation ID: 29735). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21310273, 23794683, 28712002). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs201322234, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 111 of the GFPT1 protein (p.Arg111Cys). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 11, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.70; 3Cnet: 0.62). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029735). A different missense change at the same codon (p.Arg111His) has been reported to be associated with GFPT1 related disorder (ClinVar ID: VCV001073321). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2019

- -

Congenital myasthenic syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 25, 2024

Variant summary: GFPT1 c.331C>T (p.Arg111Cys) results in a non-conservative amino acid change located in the glutamine amidotransferase type 2 domain (IPR017932) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251416 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GFPT1 causing Congenital Myasthenic Syndrome (0.00014 vs 0.0005), allowing no conclusion about variant significance. c.331C>T has been reported in the literature in the homozygous and compound heterozygous states in multiple individuals affected with Congenital Myasthenic Syndrome and segregated with disease in at least one family (e.g. Senderek_2011, Jiang_2022). These data indicate that the variant is very likely to be associated with disease. At least one in vitro study in HEK293 cells showed that this variant resulted in enzyme activity and subcellular localization that was similar to wildtype, however, it does not allow convincing conclusions about the variant effect (e.g. Senderek_2011). The following publications have been ascertained in the context of this evaluation (PMID: 34978387, 21310273). ClinVar contains an entry for this variant (Variation ID: 29735). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.058

MetaRNN

Benign

0.42

T;T

MetaSVM

Uncertain

-0.015

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.0

D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.12

T;T

Polyphen

0.71

.;P

Vest4

0.71

MVP

0.96

MPC

1.2

ClinPred

0.20

GERP RS

4.4

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.75

gMVP

0.80

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