ClinVar Genomic variation as it relates to human health
NM_177924.5(ASAH1):c.125C>T (p.Thr42Met)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_177924.5(ASAH1):c.125C>T (p.Thr42Met)
Variation ID: 35544 Accession: VCV000035544.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8p22 8: 18075541 (GRCh38) [ NCBI UCSC ] 8: 17933050 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 7, 2015 Feb 14, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_177924.5:c.125C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_808592.2:p.Thr42Met missense NM_001127505.3:c.173C>T NP_001120977.1:p.Thr58Ile missense NM_001363743.2:c.-71C>T 5 prime UTR NM_004315.5:c.173C>T NM_004315.6:c.173C>T NP_004306.3:p.Thr58Met missense NC_000008.11:g.18075541G>A NC_000008.10:g.17933050G>A NG_008985.2:g.14458C>T - Protein change
- T42M, T58M, T58I
- Other names
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- Canonical SPDI
- NC_000008.11:18075540:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ASAH1 | - | - |
GRCh38 GRCh37 |
869 | 1003 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 3, 2017 | RCV000029199.20 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2024 | RCV000724837.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 12, 2019 | RCV001270895.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 26, 2022 | RCV003390700.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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ASAH1-related disorders
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001451676.1
First in ClinVar: Dec 26, 2020 Last updated: Dec 26, 2020 |
Comment:
The ASAH1 c.173C>T (p.Thr58Met) variant is a missense variant that has been reported in four studies, in which it is found in a total of … (more)
The ASAH1 c.173C>T (p.Thr58Met) variant is a missense variant that has been reported in four studies, in which it is found in a total of 10 individuals with spinal muscular atrophy associated with progressive myoclonic epilepsy, including in eight in a homozygous state and in two in a compound heterozygous state (Zhou et al. 2012; Rubboli et al. 2015; Giráldez et al. 2015; Yildiz et al. 2018). This variant segregated with disease in two families. The p.Thr58Met variant was absent from 95 control subjects but is reported at a frequency of 0.000196 in the African population of the Genome Aggregation Database. Transient expression of the p.Thr58Met cDNA into fibroblasts derived from an individual with Farber disease demonstrated that the acid-ceramidase activity was 32% of the wild type cDNA activity. Although there was no effect on the level of the precursor form or its processing, the α-subunit amount was mildly lower than the β-subunit amount (Zhou et al. 2012). Based on the collective evidence and application of the ACMG criteria, the p.Thr58Met variant is classified as pathogenic for ASAH1-related disorders. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Spinal muscular atrophy-progressive myoclonic epilepsy syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100468.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
The missense variant p.T42M in ASAH1 (NM_177924.5) has been reported previously in affected patients (Zhou et al). Functional studies reveal a damaging effect. The p.T42M … (more)
The missense variant p.T42M in ASAH1 (NM_177924.5) has been reported previously in affected patients (Zhou et al). Functional studies reveal a damaging effect. The p.T42M variant isobserved in 2/16,256 (0.0123%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between threonine and methionine. 3 variants within 6 amino acid positions of the variant p.T42M have been shown to be pathogenic, while none have been shown to be benign. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Gowers sign (present) , Muscle weakness (present) , Myopathy (present)
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Likely pathogenic
(Aug 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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ASAH1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119531.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ASAH1 c.173C>T variant is predicted to result in the amino acid substitution p.Thr58Met. This variant (also known as c.125C>T, p.Thr42Met in transcript NM_177924.5) was … (more)
The ASAH1 c.173C>T variant is predicted to result in the amino acid substitution p.Thr58Met. This variant (also known as c.125C>T, p.Thr42Met in transcript NM_177924.5) was reported in homozygous and compound heterozygous state in several individuals with Spinal muscular atrophy associated with progressive myoclonic epilepsy (Yildiz et al. 2017. PubMed ID: 29169047; Zhou et al. 2012. PubMed ID: 22703880; Akarsu et al. 2016. PubMed ID: 27723502; Giráldez et al. 2014. PubMed ID: 25578555; Rubboli et al. 2015. PubMed ID: 25847462). Functional expression studies of the c.173C>T mutant cDNA in Farber fibroblasts showed that acid-ceramidase activity was only 32% of that generated by normal cDNA, however this reduced activity was able to normalize the ceramide level in Farber cells. Knockdown of the ASAH1 ortholog in zebrafish led to a marked loss of motor-neuron axonal branching, a loss that is associated with increased apoptosis in the spinal cord and authors assume this could be the pathogenic mechanism underlying the CNS involvement in deficient cells in case of enzyme activity reduction in this variant (Zhou et al. 2012. PubMed ID: 22703880). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-17933050-G-A). This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002211845.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 42 of the ASAH1 protein (p.Thr42Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 42 of the ASAH1 protein (p.Thr42Met). This variant is present in population databases (rs145873635, gnomAD 0.02%). This missense change has been observed in individual(s) with with spinal muscular atrophy and progressive myoclonic epilepsy (PMID: 22703880, 25578555, 25847462, 27723502). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 35544). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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Spinal muscular atrophy-progressive myoclonic epilepsy syndrome
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746510.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Age: 10-19 years
Sex: male
Geographic origin: Iran
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Pathogenic
(Jul 30, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331984.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 6
Sex: mixed
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Pathogenic
(Sep 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019452.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 13, 2012)
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no assertion criteria provided
Method: literature only
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SPINAL MUSCULAR ATROPHY WITH PROGRESSIVE MYOCLONIC EPILEPSY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000051844.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 07, 2015 |
Comment on evidence:
In 5 children from 2 families with spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME; 159950), Zhou et al. (2012) identified a homozygous 125C-T transition … (more)
In 5 children from 2 families with spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME; 159950), Zhou et al. (2012) identified a homozygous 125C-T transition in the last nucleotide of exon 2 of the ASAH1 gene, resulting in a thr42-to-met (T42M) substitution at a highly conserved residue in the alpha-subunit. The mutation was not found in 95 controls, and was found at a very low frequency (2 of 10,756 alleles) in the Exome Variant Server database. Haplotype analysis suggested a founder effect. The mutation was identified by genomewide linkage analysis followed by exome sequencing. Another patient from a third family was found to be compound heterozygous for the T42M mutation and a deletion of the ASAH1 gene (613468.0007). The T42M mutant protein was expressed in various patient tissues and showed decreased enzymatic activity (32% of controls) in in vitro functional studies, although the mutant enzyme still showed activity toward ceramide. Immunoblot experiments showed that the amount of the alpha-subunit was mildly lower than the beta subunit, suggesting that the mutation may affect the stability of the alpha-subunit and thus contribute to decreased enzyme activity. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Spinal muscular atrophy-progressive myoclonic epilepsy syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000778526.5
First in ClinVar: May 03, 2018 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Spinal muscular atrophy with progressive myoclonic epilepsy linked to mutations in ASAH1. | Yildiz EP | Clinical neurology and neurosurgery | 2018 | PMID: 29169047 |
Eyelid myoclonic status epilepticus: A rare phenotype in spinal muscular atrophy with progressive myoclonic epilepsy associated with ASAH1 gene mutation. | Oguz Akarsu E | Seizure | 2016 | PMID: 27723502 |
Spinal muscular atrophy associated with progressive myoclonic epilepsy: A rare condition caused by mutations in ASAH1. | Rubboli G | Epilepsia | 2015 | PMID: 25847462 |
Uniparental disomy as a cause of spinal muscular atrophy and progressive myoclonic epilepsy: phenotypic homogeneity due to the homozygous c.125C>T mutation in ASAH1. | Giráldez BG | Neuromuscular disorders : NMD | 2015 | PMID: 25578555 |
Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1. | Zhou J | American journal of human genetics | 2012 | PMID: 22703880 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ASAH1 | - | - | - | - |
Text-mined citations for rs145873635 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.