rs201322234

Variant names:

• chr2-69363563-G-A
• rs201322234
• NM_001244710.2:c.331C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM5 PP2 PP5 BP4

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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R111H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: GFPT1 NM_001244710.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 1.41

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-69363562-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1073321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.3482 (above the threshold of 3.09). Trascript score misZ: 4.3487 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 29735.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3, Pathogenic=2}. 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 rank	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.331C>T	p.Arg111Cys	missense_variant	Exon 4 of 20	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.331C>T	p.Arg111Cys	missense_variant	Exon 4 of 19		NP_002047.2
GFPT1	XM_017003801.2	c.406C>T	p.Arg136Cys	missense_variant	Exon 4 of 20		XP_016859290.1
GFPT1	XM_017003802.3	c.406C>T	p.Arg136Cys	missense_variant	Exon 4 of 19		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.331C>T	p.Arg111Cys	missense_variant	Exon 4 of 20	5	NM_001244710.2	ENSP00000349860.4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152100 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251416 AF XY: 0.000125

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 FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461738 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 727168

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33476

Gnomad4 AMR exome AF: 0.000447 AC: 20 AN: 44722

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26130

Gnomad4 EAS exome AF: 0.000126 AC: 5 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86254

Gnomad4 FIN exome AF: 0.0000374 AC: 2 AN: 53414

Gnomad4 NFE exome AF: 0.0000162 AC: 18 AN: 1111888

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74424

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00262 AC: 0.00261677 AN: 0.00261677

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.00019305 AN: 0.00019305

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000588045 AN: 0.0000588045

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.000291

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 12 Pathogenic:4 Uncertain:1

Mar 02, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs201322234, gnomAD 0.06%). 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. ClinVar contains an entry for this variant (Variation ID: 29735). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GFPT1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Feb 11, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 14, 2024

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM5_Supporting, PM1_Supporting, PM2_Supporting, PM3_Supporting -

Feb 23, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome Pathogenic:1

Jun 25, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	-0.015	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.81	D
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	T
GERP RS		4.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.75
gMVP		0.80
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs201322234; hg19: chr2-69590695; COSMIC: COSV100623002; COSMIC: COSV100623002;