rs199877522

chr9-36227397-C-Achr9-36227397-C-Gchr9-36227397-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM5 PP2 PP5

The NM_001128227.3(GNE):c.1225G>T(p.Asp409Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,612,536 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D409E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: GNE NM_001128227.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1 O:2
• Conservation: PhyloP100: 2.90

Genes affected

GNE (HGNC:23657): (glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase) The protein encoded by this gene is a bifunctional enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids. It is a rate-limiting enzyme in the sialic acid biosynthetic pathway. Sialic acid modification of cell surface molecules is crucial for their function in many biologic processes, including cell adhesion and signal transduction. Differential sialylation of cell surface molecules is also implicated in the tumorigenicity and metastatic behavior of malignant cells. Mutations in this gene are associated with sialuria, autosomal recessive inclusion body myopathy, and Nonaka myopathy. Alternative splicing of this gene results in transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

CLTA (HGNC:2090): (clathrin light chain A) Clathrin is a large, soluble protein composed of heavy and light chains. It functions as the main structural component of the lattice-type cytoplasmic face of coated pits and vesicles which entrap specific macromolecules during receptor-mediated endocytosis. This gene encodes one of two clathrin light chain proteins which are believed to function as regulatory elements. Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 8 and 12. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a strand (size 8) in uniprot entity GLCNE_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001128227.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-36227397-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1324492.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, GNE
• PP5: Variant 9-36227397-C-A is Pathogenic according to our data. Variant chr9-36227397-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283278.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=9, not_provided=2, Uncertain_significance=1}. Variant chr9-36227397-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNE	NM_001128227.3	c.1225G>T	p.Asp409Tyr	missense_variant	7/12	ENST00000396594.8
GNE	NM_005476.7	c.1132G>T	p.Asp378Tyr	missense_variant	7/12	ENST00000642385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNE	ENST00000396594.8	c.1225G>T	p.Asp409Tyr	missense_variant	7/12	1	NM_001128227.3
GNE	ENST00000642385.2	c.1132G>T	p.Asp378Tyr	missense_variant	7/12		NM_005476.7	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.000368

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000159 AC: 40 AN: 251400 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135888

Gnomad AFR exome AF: 0.0000616

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: 0.000343

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000393 AC: 574 AN: 1460430 Hom.: 0 Cov.: 30 AF XY: 0.000356 AC XY: 259 AN XY: 726622

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000475

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74302

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000960

Alfa AF: 0.000238 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

GNE myopathy Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 09, 2018	Variants in the GNE gene are known to cause GNE-related myopathies. The GNE c.1132G>T (p.Asp378Tyr) missense variant has been reported in at least three studies in which it is found in a compound heterozygous state in a total of five individuals with GNE-related myopathy (two of whom were related) (Eisenberg et al. 2003; Nishino et al. 2002; Leoyklang et al. 2014). The p.Asp378Tyr variant was absent from 50 control subjects and is reported at a frequency of 0.000324 in the European (non-Finnish) population of the Genome Aggregation Database. In vitro studies showed that p.Asp378Tyr variant was associated with 60% reduction of epimerase and a 50% reduction of kinase activity compared to wild type (Penner et al., 2006). Based on the evidence, the p.Asp378Tyr variant is classified as pathogenic for GNE-related myopathies. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2024	Variant summary: GNE c.1225G>T (p.Asp409Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251400 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.1225G>T has been reported in the literature in multiple individuals affected with Inclusion Body Myopathy 2 (Noguchi_2004, Pogoryelova_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in reduced enzyme activity (Noguchi_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 30842975). ClinVar contains an entry for this variant (Variation ID: 283278). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	NM_001128227.2(GNE):c.1225G>T(D409Y) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 12473753, 24695763, 14707127 and 16503651. Classification of NM_001128227.2(GNE):c.1225G>T(D409Y) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 25, 2016	The p.Asp409Tyr variant in GNE has been reported in at least 12 compound heteroz ygous patients from 9 families (Chaouch 2014). In addition, this variant has bee n identified in 0.01% (14/121,022) of chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs199877522). Although this v ariant has been seen in the general population, its frequency is low enough to b e consistent with a carrier frequency. In vitro functional studies support an im pact to protein function (Noguchi 2004, Penner 2006). In summary, this variant m eets criteria to be classified as pathogenic for GNE-related myopathy based on g enetic and functional data. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2022	Published functional studies demonstrate a damaging effect (60% reduction in epimerase activity and 50% reduction in kinase activity as compared to wild type) (Penner et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29305133, 12497639, 24695763, 16503651, 14707127, 12473753, 29382405, 19917666, 30467490, 30609409, 31127727, 24796702, 19596068, 27829678, 25123033, 24027297, 20301439, 29997562, 28641925, 30564623, 12325084, 26968811) -

Sialuria;C1853926:GNE myopathy Pathogenic:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 07-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 409 of the GNE protein (p.Asp409Tyr). This variant is present in population databases (rs199877522, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive GNE-related myopathy (PMID: 12473753, 12497639, 24695763). It is commonly reported in individuals of European ancestry (PMID: 12473753, 12497639, 24695763). This variant is also known as p.D378Y. ClinVar contains an entry for this variant (Variation ID: 283278). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNE protein function. Experimental studies have shown that this missense change affects GNE function (PMID: 14707127, 16503651). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

The c.1225G>T (p.D409Y) alteration is located in coding exon 7 of the GNE gene. This alteration results from a G to T substitution at nucleotide position 1225, causing the aspartic acid (D) at amino acid position 409 to be replaced by a tyrosine (Y)._x000D_ _x000D_ Based on the available evidence, the GNE c.1225G>T (p.D409Y) alteration is classified as pathogenic for autosomal recessive Nonaka myopathy; however, its clinical significance for autosomal dominant sialuria is uncertain. Based on data from gnomAD, the T allele has an overall frequency of 0.016% (45/282778) total alleles studied. The highest observed frequency was 0.033% (42/129128) of European (non-Finnish) alleles. This variant has been described as a British founder mutation after being reported in compound heterozygous form in numerous individuals affected with clinical and pathological findings consistent with GNE-related myopathy (Chaouch, 2014; Carrillo, 2018; Soule, 2018). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Sialuria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;D;.;.;.;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.81	L;.;L;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
Polyphen		1.0	D;D;D;.;.;.;D
Vest4		0.87, 0.88, 0.83, 0.79, 0.75, 0.87
MVP		0.99
MPC		1.6
ClinPred		0.43	T
GERP RS		6.0
Varity_R		0.90
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs199877522; hg19: chr9-36227394; COSMIC: COSV64951187;