2-69326167-G-T

Variant names:

• chr2-69326167-G-T
• rs199678034
• NM_001244710.2:c.*22C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3 PP5 BS2

The NM_001244710.2(GFPT1):​c.*22C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,511,390 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: GFPT1 NM_001244710.2 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:2
• Conservation: PhyloP100: 0.525
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 12

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Illumina
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-69326167-G-T is Pathogenic according to our data. Variant chr2-69326167-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 208585.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244710.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFPT1	NM_001244710.2	MANE Select	c.*22C>A		3_prime_UTR	Exon 20 of 20	NP_001231639.1
	GFPT1	NM_002056.4		c.*22C>A		3_prime_UTR	Exon 19 of 19	NP_002047.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFPT1	ENST00000357308.9	TSL:5 MANE Select	c.*22C>A		3_prime_UTR	Exon 20 of 20	ENSP00000349860.4
	GFPT1	ENST00000361060.5	TSL:1	c.*22C>A		3_prime_UTR	Exon 19 of 19	ENSP00000354347.4
	GFPT1	ENST00000674507.1		c.*22C>A		3_prime_UTR	Exon 18 of 18	ENSP00000501332.1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 216 AN: 151010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000414

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00245

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000293

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.00133 AC: 333 AN: 249944 AF XY: 0.00138

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.000987

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000330

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00203 AC: 2761 AN: 1360264 Hom.: 5 Cov.: 22 AF XY: 0.00193 AC XY: 1315 AN XY: 682390

African (AFR) AF: 0.000414 AC: 13 AN: 31436

American (AMR) AF: 0.00117 AC: 52 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.0000786 AC: 2 AN: 25430

East Asian (EAS) AF: 0.00 AC: 0 AN: 39130

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83798

European-Finnish (FIN) AF: 0.000323 AC: 17 AN: 52572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.00251 AC: 2563 AN: 1021002

Other (OTH) AF: 0.00199 AC: 113 AN: 56908

GnomAD4 genome AF: 0.00142 AC: 215 AN: 151126 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 102 AN XY: 73708

African (AFR) AF: 0.000413 AC: 17 AN: 41138

American (AMR) AF: 0.00244 AC: 37 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.000293 AC: 3 AN: 10244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00227 AC: 154 AN: 67892

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.000502 Hom.: 0

Bravo AF: 0.00165

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 12 Pathogenic:6

Feb 25, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 04, 2025

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 29, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Apr 12, 2020

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the GFPT1 gene. It does not change the encoded amino acid sequence of the GFPT1 protein. This variant is present in population databases (rs199678034, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21310273, 23488891, 23794683). 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: 208585). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GFPT1 function (PMID: 21310273, 25765662). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:4 Uncertain:1

Sep 26, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect with the formation of a microRNA binding site resulting in reduced protein expression (PMID: 25765662); This variant is associated with the following publications: (PMID: 21310273, 26501342, 23488891, 27472506, 21975507, 26721333, 28754144, 29054425, 31047772, 23794683, 34978387, 36188410, 25765662, 28712002, 38235042, 37721175, 40442802)

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 31, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GFPT1: PM3:Strong, PP1:Strong, PM2:Supporting, PS3:Supporting

Congenital myasthenic syndrome Pathogenic:1

Sep 04, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GFPT1 c.*22C>A is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.002 in 1504712 control chromosomes, predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in GFPT1 causing Congenital Myasthenic Syndrome (CMS) phenotype (0.0005). The observed relatively high frequency in non-Finnish Europeans, together with the homozygous occurrences, might indicate a benign nature for the variant. However, the variant c.*22C>A has also been reported in the literature in numerous compound heterozygous individuals, who were affected with Congenital Myasthenic Syndrome, including multiple cases where the variant segregated with disease (e.g. Senderek_2011, Selcen_2013, Maselli_2014, Natera-de Benito_2017, Bauche_2017). These data indicate that the variant is likely to be associated with disease, although the pathogenicity of the variant might be dependent on the variant observed in trans. At least two publications report that GFPT1 protein, but not mRNA levels, are reduced in muscle cells from patients harboring the c.*22C>A variant compared to healthy control individuals (e.g. Senderek_2011, Dusl_2015) and a similar relationship was observed in myoblasts expressing the variant compared to wild-type (Dusl_2015). One of these publications also provided evidence to support that the variant may allow for binding of a microRNA, that is expressed in myoblasts, myotubes and skeletal muscle, which may cause the reduction in GFPT1 protein expression by repressing translation (Dusl_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25765662, 23488891, 23794683, 21310273, 29054425, 28712002). ClinVar contains an entry for this variant (Variation ID: 208585). Based on the evidence outlined above, the variant likely represents a hypomorphic allele, which in compound heterozygous state, together with other (likely more severe) variants in trans, can cause CMS and related phenotypes, therefore, the variant was classified as likely pathogenic.

not specified Uncertain:1

Feb 27, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The c.*22C>A variant in GFPT1 has been reported in 8 individuals with features of limb-girdle myasthenic syndrome (Senderek 2011, Selcen 2013, Bauche 2017, Natera-de Benito 2017). All of these individuals carried second variants in the GFPT1 gene; however, in only 3 of these probands were the variants confirmed to be in trans and have sufficient evidence to be classified as likely pathogenic or pathogenic(Senderek 2011, Selcen 2013). Furthermore, the variant segregated with disease in 7 affected individuals from 5 families (Senderek 2011, Selcen 2013). It has also been identified in 0.23% (297/128550) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has been reported with conflicting interpretations in ClinVar (Variant ID 208585). This variant is located in the 3' untranslated region. In vitro functional studies provide some evidence that the c.*22C>A variant may lead to reduced GFPT1 protein levels by influencing miRNA binding and thereby protein translation (Senderek 2011, Muller 2012, Dusl 2015). However, the assay may not accurately represent the in vivo environment and the reduction in protein levels may not be sufficient for disease. While the biallelic occurrences, segregation in affected individuals, and in vitro functional studies support a disease-causing role, given the relatively high frequency of this variant in the general population, there is some concern that the biallelic occurrences may have been seen by chance (therefore the PM3 evidence was downgraded) or that the variant may be in linkage disequilibrium with another pathogenic variant in the families described (therefore PP1 evidence was downgraded). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the c.*22C>A variant is uncertain. ACMG/AMP guidelines applied: BS1_Supporting, PM3_Supporting, PP1_Moderate, PS3_Supporting.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.58
PhyloP100		0.53
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.59		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199678034; hg19: chr2-69553299;