rs764317969
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_000543.5(SMPD1):āc.680T>Cā(p.Leu227Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,609,088 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L227M) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000543.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMPD1 | NM_000543.5 | c.680T>C | p.Leu227Pro | missense_variant | 2/6 | ENST00000342245.9 | NP_000534.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMPD1 | ENST00000342245.9 | c.680T>C | p.Leu227Pro | missense_variant | 2/6 | 1 | NM_000543.5 | ENSP00000340409 | P3 |
Frequencies
GnomAD3 genomes AF: 0.00000668 AC: 1AN: 149790Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000405 AC: 1AN: 246886Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134162
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459298Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 726076
GnomAD4 genome AF: 0.00000668 AC: 1AN: 149790Hom.: 0 Cov.: 31 AF XY: 0.0000137 AC XY: 1AN XY: 72922
ClinVar
Submissions by phenotype
Niemann-Pick disease, type A Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 25, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 01, 2017 | - - |
Niemann-Pick disease, type B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS | Apr 25, 2021 | - - |
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2023 | 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 expected to disrupt SMPD1 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 16010684, 19405096). ClinVar contains an entry for this variant (Variation ID: 553073). This variant is also known as c.674T>C (p.L225P). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 15241805, 34273913). This variant is present in population databases (rs764317969, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 227 of the SMPD1 protein (p.Leu227Pro). - |
Sphingomyelin/cholesterol lipidosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 22, 2021 | Variant summary: SMPD1 c.680T>C (p.Leu227Pro) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type domain (IPR004843) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247098 control chromosomes (gnomAD and publication data). c.680T>C has been reported in the literature in individuals affected with Niemann-Pick Disease (Pittis_2004, Bonetto_2005, Zanetti_2020). These data indicate that the variant may be associated with disease. At least two functional papers report this variant results in deficient activity of acid sphingomyelinase (Dardis_2005, Rodrguez-Pascau_2009). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at