rs104893982

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000434.4(NEU1):c.649G>A(p.Val217Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V217A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

NEU1
NM_000434.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.02

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:

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;

PP5

Variant 6-31860588-C-T is Pathogenic according to our data. Variant chr6-31860588-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31860588-C-T is described in UniProt as null. Variant chr6-31860588-C-T is described in UniProt as null. Variant chr6-31860588-C-T is described in UniProt as null. Variant chr6-31860588-C-T is described in UniProt as null. Variant chr6-31860588-C-T is described in UniProt as null. Variant chr6-31860588-C-T is described in UniProt as null. Variant chr6-31860588-C-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEU1	NM_000434.4 linkuse as main transcript	c.649G>A	p.Val217Met	missense_variant	4/6	ENST00000375631.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEU1	ENST00000375631.5 linkuse as main transcript	c.649G>A	p.Val217Met	missense_variant	4/6	1	NM_000434.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000558

AC:

AN:

250988

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.000740

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000164

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

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:

0.0000874

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

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

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 21, 2023	PP1, PM2, PM3, PS3, PS4_moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2017	The V217M variant in the NEU1 gene has previously been reported in two unrelated individuals with late-onset sialidosis who were also compound heterozygous for another variant in the NEU1 gene (Naganawa et al., 2000). Functional analysis of V217M found that it is associated with significantly reduced, but not absent enzyme activity compared to wild-type (Naganawa et al., 2000). Therefore we interpret V217M to be a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 217 of the NEU1 protein (p.Val217Met). This variant is present in population databases (rs28940583, gnomAD 0.07%). This missense change has been observed in individual(s) with sialidosis type I (PMID: 10944856, 32485644). ClinVar contains an entry for this variant (Variation ID: 2449). 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: 10944856, 11829139). 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

Dec 13, 2023

Variant summary: NEU1 c.649G>A (p.Val217Met) results in a 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 5.9e-05 in 253430 control chromosomes (gnomAD and Kausthubham_2021). This frequency is not higher than expected for a pathogenic variant in NEU1 causing Sialidosis (5.9e-05 vs 0.0011), allowing no conclusion about variant significance. c.649G>A has been reported in the literature in at least three individuals affected with Sialidosis, type I (e.g. Naganawa_2000, Han_2020, Riboldi_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant was partly transported to lysosomes, and showed some residual enzyme activity (Naganawa_2000). The following publications have been ascertained in the context of this evaluation (PMID: 32485644, 33502066, 10944856, 34992946, 16538002). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Sialidosis type 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0070

Polyphen

0.97

Vest4

0.94

MVP

0.96

MPC

1.3

ClinPred

0.24

GERP RS

5.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.45

gMVP

0.79

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