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UniProtKB/Swiss-Prot P17405: Variant p.Arg498Leu

Sphingomyelin phosphodiesterase
Gene: SMPD1
Variant information

Variant position:  498
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  LP/P [Disclaimer]
The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance

Residue change:  From Arginine (R) to Leucine (L) at position 498 (R498L, p.Arg498Leu).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from large size and basic (R) to medium size and hydrophobic (L)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -2
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Variant description:  In NPDA; in 32% of NPDA Ashkenazi Jewish patients; nearly abolishes enzyme activity.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  498
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  631
The length of the canonical sequence.

Location on the sequence:   LAVAFLAPSATTYIGLNPGY  R VYQIDGNYSGSSHVVLDHET
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         LAVAFLAPSATTYIGLNPGYRVYQIDGNYSGSSHVVLDHET

Mouse                         LAVAFLAPSATTFINLNPGYRVYQIDGNYPGSSHVVLDHET

Bovine                        LSVAFLAPSATTYIGLNPGYRVYQIDGNYSGSSHVVLDHET

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 47 – 631 Sphingomyelin phosphodiesterase
Modified residue 510 – 510 Phosphoserine; by PKC/PRKCD
Glycosylation 505 – 505 N-linked (GlcNAc...) asparagine
Mutagenesis 505 – 505 N -> G. Loss of sphingomyelin phosphodiesterase activity. Loss of secretion.
Mutagenesis 510 – 510 S -> A. Abolishes constitutive secretion and decreases secretion in response to IL1B. No effect on lysosomal targeting. No effect on sphingomyelin phosphodiesterase activity. No effect on endolysosome location. Abolishes phosphorylation by PRKCD.
Beta strand 496 – 503


Literature citations

Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients.
Levran O.; Desnick R.J.; Schuchman E.H.;
Proc. Natl. Acad. Sci. U.S.A. 88:3748-3752(1991)
Cited for: VARIANT NPDA LEU-498;

The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene.
Schissel S.L.; Keesler G.A.; Schuchman E.H.; Williams K.J.; Tabas I.;
J. Biol. Chem. 273:18250-18259(1998)
Cited for: CHARACTERIZATION OF VARIANT NPDA LEU-498; FUNCTION; COFACTOR;

Screening of 25 Italian patients with Niemann-Pick A reveals fourteen new mutations, one common and thirteen private, in SMPD1.
Ricci V.; Stroppiano M.; Corsolini F.; Di Rocco M.; Parenti G.; Regis S.; Grossi S.; Biancheri R.; Mazzotti R.; Filocamo M.;
Hum. Mutat. 24:105-105(2004)
Cited for: VARIANTS NPDA PRO-105; SER-247; LYS-248; HIS-315; PRO-452; LEU-477; LEU-498; HIS-498 AND CYS-519; VARIANT GLN-296;

Characterization of common SMPD1 mutations causing types A and B Niemann-Pick disease and generation of mutation-specific mouse models.
Jones I.; He X.; Katouzian F.; Darroch P.I.; Schuchman E.H.;
Mol. Genet. Metab. 95:152-162(2008)
Cited for: CHARACTERIZATION OF VARIANTS NPDA PRO-304 AND LEU-498; CHARACTERIZATION OF VARIANTS NPDB TYR-423 AND ARG-610 DEL; FUNCTION; SUBCELLULAR LOCATION; CATALYTIC ACTIVITY;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.