rs104893981

chr6-31860170-G-Achr6-31860170-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.94

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000434.4
• 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	UniProt
NEU1	NM_000434.4	c.893C>T	p.Ala298Val	missense_variant	5/6	ENST00000375631.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEU1	ENST00000375631.5	c.893C>T	p.Ala298Val	missense_variant	5/6	1	NM_000434.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 32

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: 10 AN: 246526 Hom.: 0 AF XY: 0.0000447 AC XY: 6 AN XY: 134342

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: 37 AN: 1460770 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 726696

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: 3 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74306

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.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000333 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sialidosis type 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -
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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

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	D
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.76	A
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.79	P
Vest4		0.79
MutPred		0.85		Loss of sheet (P = 0.1907);
MVP		0.93
MPC		1.3
ClinPred		0.49	T
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

Other links and lift over

dbSNP: rs104893981; hg19: chr6-31827947;