rs1555538144
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000049.4(ASPA):c.89T>C(p.Leu30Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 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. L30V) has been classified as Pathogenic.
Frequency
Consequence
NM_000049.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASPA | NM_000049.4 | c.89T>C | p.Leu30Pro | missense_variant | 1/6 | ENST00000263080.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPA | ENST00000263080.3 | c.89T>C | p.Leu30Pro | missense_variant | 1/6 | 1 | NM_000049.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Spongy degeneration of central nervous system Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2019 | 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. This variant has been reported to affect ASPA protein function (PMID: 28101991). This variant has been observed in the homozygous state in an individual affected with Canavan disease (PMID: 28101991). ClinVar contains an entry for this variant (Variation ID: 556181). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 30 of the ASPA protein (p.Leu30Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Jan 17, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Canavan Disease, Familial Form Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 11, 2023 | Variant summary: ASPA c.89T>C (p.Leu30Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251468 control chromosomes. c.89T>C has been reported in the literature in at least one homozygous individual affected with Canavan Disease (e.g., Mendes_2017). Experimental evidence evaluating an impact on protein function, found that HEK293 cells transfected with the variant protein displayed <1% enzymatic activity (Mendes_2017). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) have cited the variant, with two submitters classifying is as likely pathogenic, and one submitter classifying it as uncertain significance. 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