Submissions for variant NM_000434.4(NEU1):c.649G>A (p.Val217Met)

gnomAD frequency: 0.00017  dbSNP: rs28940583

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000480504	SCV000337112	likely pathogenic	not provided	2015-11-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000480504	SCV000568559	pathogenic	not provided	2017-01-28	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000480504	SCV000801710	pathogenic	not provided	2023-04-21	criteria provided, single submitter	clinical testing	PP1, PM2, PM3, PS3, PS4_moderate
Invitae	RCV000480504	SCV001575977	likely pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281689	SCV002570597	likely pathogenic	Sialidosis	2023-12-13	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000002553	SCV000022711	pathogenic	Sialidosis type 1	2000-01-01	no assertion criteria provided	literature only