ClinVar Genomic variation as it relates to human health
NM_000344.4(SMN1):c.5C>G (p.Ala2Gly)
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_000344.4(SMN1):c.5C>G (p.Ala2Gly)
Variation ID: 9168 Accession: VCV000009168.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q13.2 5: 70925108 (GRCh38) [ NCBI UCSC ] 5: 70220935 (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 Apr 4, 2013 Jan 26, 2024 Sep 21, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000344.4:c.5C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000335.1:p.Ala2Gly missense NM_001297715.1:c.5C>G NP_001284644.1:p.Ala2Gly missense NM_022874.2:c.5C>G NP_075012.1:p.Ala2Gly missense NC_000005.10:g.70925108C>G NC_000005.9:g.70220935C>G NG_008691.1:g.5168C>G LRG_676:g.5168C>G LRG_676t1:c.5C>G LRG_676p1:p.Ala2Gly Q16637:p.Ala2Gly - Protein change
- A2G
- Other names
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- Canonical SPDI
- NC_000005.10:70925107:C:G
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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.
The Genome Aggregation Database (gnomAD) 0.00571
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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SMN1 | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh37 |
161 | 224 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (1) |
no assertion criteria provided
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Dec 1, 1998 | RCV000009739.2 | |
Pathogenic (2) |
criteria provided, single submitter
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Feb 26, 2016 | RCV000009740.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2022 | RCV000517884.5 |
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
(Sep 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000615352.4
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
Frequency data for this variant in the Genome Aggregation Database (gnomAD) cannot be distinguished from that of the SMN2 gene, and is therefore uninformative in … (more)
Frequency data for this variant in the Genome Aggregation Database (gnomAD) cannot be distinguished from that of the SMN2 gene, and is therefore uninformative in assessment of variant pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple individuals with SMA types II, III, or IV who also carried a heterozygous pathogenic deletion of exon 7 in the SMN1 gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12515823) (less)
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Pathogenic
(Feb 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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Kugelberg-Welander disease
Affected status: yes
Allele origin:
unknown
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Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000924366.1
First in ClinVar: Jun 23, 2019 Last updated: Jun 23, 2019 |
Observation 1:
Number of individuals with the variant: 1
Age: 10-19 years
Sex: male
Observation 2:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Comment on evidence:
hypotonia, electromyogram consistent with spinal muscular atrophy, 1 copy each SMN1 and SMN2
Observation 3:
Number of individuals with the variant: 1
Age: 20-29 years
Sex: female
Comment on evidence:
clinical diagnosis of spinal muscular atrophy Type III
Observation 4:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Comment on evidence:
negative for homozygous deletion, muscle weakness in all extremities, possible axonal neuropathy
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
proximal muscle weakness (present)
Age: 10-19 years
Sex: male
Comment on evidence:
1 copy of SMN1
Observation 6:
Number of individuals with the variant: 1
Clinical Features:
right lower extremity weakness (present) , atrophy (present)
Age: 10-19 years
Sex: female
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Pathogenic
(Dec 01, 1998)
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no assertion criteria provided
Method: literature only
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SPINAL MUSCULAR ATROPHY, TYPE II
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029960.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 3 unrelated patients, 1 with SMA type II (253550) and 2 with SMA type III (253400), Parsons et al. (1998) identified a 38C-G transversion … (more)
In 3 unrelated patients, 1 with SMA type II (253550) and 2 with SMA type III (253400), Parsons et al. (1998) identified a 38C-G transversion in exon 1 of the SMN1 gene, resulting in an ala2-to-gly (A2G) substitution. The base change produced a new restriction-enzyme site within exon 1, allowing other individuals to be screened for the mutation. The 3 patients with the A2G missense mutation also had a C-to-T polymorphism in the SMN1 gene, 14-bp upstream of exon 1 in the 5-prime UTR, providing evidence for a founder chromosome. (less)
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Pathogenic
(Dec 01, 1998)
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no assertion criteria provided
Method: literature only
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SPINAL MUSCULAR ATROPHY, TYPE III
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029961.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 3 unrelated patients, 1 with SMA type II (253550) and 2 with SMA type III (253400), Parsons et al. (1998) identified a 38C-G transversion … (more)
In 3 unrelated patients, 1 with SMA type II (253550) and 2 with SMA type III (253400), Parsons et al. (1998) identified a 38C-G transversion in exon 1 of the SMN1 gene, resulting in an ala2-to-gly (A2G) substitution. The base change produced a new restriction-enzyme site within exon 1, allowing other individuals to be screened for the mutation. The 3 patients with the A2G missense mutation also had a C-to-T polymorphism in the SMN1 gene, 14-bp upstream of exon 1 in the 5-prime UTR, providing evidence for a founder chromosome. (less)
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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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Phenotypes of SMA patients retaining SMN1 with intragenic mutation. | Wijaya YOS | Brain & development | 2021 | PMID: 33892995 |
Clinical and radiological profile of patients with spinal muscular atrophy type 4. | Souza PVS | European journal of neurology | 2021 | PMID: 33090613 |
Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy. | Mendonça RH | Neurology. Genetics | 2020 | PMID: 33062891 |
Mutation Spectrum of the Survival of Motor Neuron 1 and Functional Analysis of Variants in Chinese Spinal Muscular Atrophy. | Qu YJ | The Journal of molecular diagnostics : JMD | 2016 | PMID: 27425821 |
A new method for SMN1 and hybrid SMN gene analysis in spinal muscular atrophy using long-range PCR followed by sequencing. | Kubo Y | Journal of human genetics | 2015 | PMID: 25716911 |
Ubiquitin-specific protease 9x deubiquitinates and stabilizes the spinal muscular atrophy protein-survival motor neuron. | Han KJ | The Journal of biological chemistry | 2012 | PMID: 23112048 |
Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. | Dominguez E | Human molecular genetics | 2011 | PMID: 21118896 |
Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. | Kariya S | Human molecular genetics | 2008 | PMID: 18492800 |
Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. | Gabanella F | PloS one | 2007 | PMID: 17895963 |
A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy. | Monani UR | The Journal of cell biology | 2003 | PMID: 12515823 |
Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number. | Parsons DW | American journal of human genetics | 1998 | PMID: 9837824 |
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Text-mined citations for rs1554066397 ...
HelpRecord last updated May 08, 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.