rs104893981

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000434.4(NEU1):c.893C>T(p.Ala298Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,612,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

NEU1
NM_000434.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.94

Variant links:

Genes affected

NEU1 (HGNC:7758): (neuraminidase 1) The protein encoded by this gene is a lysosomal enzyme that cleaves terminal sialic acid residues from substrates such as glycoproteins and glycolipids. In the lysosome, this enzyme is part of a heterotrimeric complex together with beta-galactosidase and cathepsin A (the latter is also referred to as 'protective protein'). Mutations in this gene can lead to sialidosis, a lysosomal storage disease that can be type 1 (cherry red spot-myoclonus syndrome or normosomatic type), which is late-onset, or type 2 (the dysmorphic type), which occurs at an earlier age with increased severity. [provided by RefSeq, Jul 2008]

NEU1 links:

NEU1 (HGNC:):

NEU1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

PP5

Variant 6-31860170-G-A is Pathogenic according to our data. Variant chr6-31860170-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31860170-G-A is described in UniProt as null. Variant chr6-31860170-G-A is described in UniProt as null. Variant chr6-31860170-G-A is described in UniProt as null. Variant chr6-31860170-G-A is described in UniProt as null. Variant chr6-31860170-G-A is described in UniProt as null. Variant chr6-31860170-G-A is described in UniProt as null. Variant chr6-31860170-G-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEU1	NM_000434.4 linkuse as main transcript	c.893C>T	p.Ala298Val	missense_variant	5/6	ENST00000375631.5	NP_000425.1	Q99519Q5JQI0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEU1	ENST00000375631.5 linkuse as main transcript	c.893C>T	p.Ala298Val	missense_variant	5/6	1	NM_000434.4	ENSP00000364782.4		Q99519

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000406

AC:

AN:

246526

Hom.:

AF XY:

0.0000447

AC XY:

AN XY:

134342

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000601

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1460770

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726696

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000995

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000997

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000333

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sialidosis type 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 29, 2016	The NEU1 c.893C>T (p.Ala298Val) missense variant has been reported in two individuals with mucolipidosis, type 1, including one who carried the variant in a homozygous state and one who carried the variant in a compound heterozygous state (Lukong et al. 2000; Pattison et al. 2004). The p.Ala298Val was absent from 20 controls and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies using COS-7 cells and sialidosis-deficient human fibroblasts demonstrated that the p.Ala298Val variant has very low sialidase activity compared to wild type NEU1, and the p.Ala298Val variant also results in aberrant localization of the NEU1 protein, likely due to protein misfolding (Lukong et al. 2000; Pattison et al. 2004). Based on the evidence, the p.Ala298Val variant is classified as likely pathogenic for mucolipidosis, type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 298 of the NEU1 protein (p.Ala298Val). This variant is present in population databases (rs104893981, gnomAD 0.07%). This missense change has been observed in individual(s) with sialidosis (PMID: 10767332, 14695530). ClinVar contains an entry for this variant (Variation ID: 2457). 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 NEU1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NEU1 function (PMID: 10767332, 11279074, 14695530). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Sialidosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 24, 2023

Variant summary: NEU1 c.893C>T (p.Ala298Val) results in a non-conservative amino acid change located in the Sialidase domain (IPR011040) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 246526 control chromosomes (gnomAD v2.1 Exomes dataset). This frequency is not significantly higher than estimated for a pathogenic variant in NEU1 causing Sialidosis (4.1e-05 vs 0.0011), allowing no conclusion about variant significance. c.893C>T has been reported in the literature in at least one homozygote and one compound heterozygote affected with Sialidosis (e.g., Lukong_2000, Pattison_2004). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in <10% enzymatic activity, which is likely due to protein misfolding (e.g, Lukong_2000, Lukong_2001, Pattison_2004). The following publications have been ascertained in the context of this evaluation (PMID: 10767332, 11279074, 14695530). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.76

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-0.32

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.63

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.79

Vest4

0.79

MutPred

0.85

Loss of sheet (P = 0.1907);

MVP

0.93

MPC

1.3

ClinPred

0.49

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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