VCV000009166.7 - ClinVar

NM_000344.4(SMN1):c.815A>G (p.Tyr272Cys)

Germline

Classification

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.

(4)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000344.4(SMN1):c.815A>G (p.Tyr272Cys)

Variation ID: 9166 Accession: VCV000009166.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q13.2 5: 70946157 (GRCh38) [ NCBI UCSC ] 5: 70241984 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jun 26, 2017	Jan 26, 2024	Jun 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000344.4:c.815A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000335.1:p.Tyr272Cys	missense
NM_001297715.1:c.815A>G	NP_001284644.1:p.Tyr272Cys	missense
NM_022874.2:c.719A>G	NP_075012.1:p.Tyr240Cys	missense
NC_000005.10:g.70946157A>G
NC_000005.9:g.70241984A>G
NG_008691.1:g.26217A>G
LRG_676:g.26217A>G
LRG_676t1:c.815A>G	LRG_676p1:p.Tyr272Cys
	Q16637:p.Tyr272Cys

... more HGVS ... less HGVS

Protein change

Y272C, Y240C

Other names

Canonical SPDI

NC_000005.10:70946156:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA254677 UniProtKB: Q16637#VAR_005617 OMIM: 600354.0004 dbSNP: rs104893922 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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.
SMN1		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	164	227

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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Werdnig-Hoffmann disease	Likely pathogenic (2)	criteria provided, single submitter	Mar 1, 2016	RCV000009737.6
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 1, 2023	RCV000518253.5
Spinal muscular atrophy	Pathogenic (1)	criteria provided, single submitter	Feb 2, 2022	RCV002470706.1

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 Help 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.
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinal muscular atrophy (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002769403.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (4) PubMed: 7813012‚ 10205265‚ 10679938‚ 31301241 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spinal muscular atrophy. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0501 - Missense variant is highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most common pathogenic variants reported in patients with spinal muscular atrophy (PMID: 7813012, 10205265, 10679938, 31301241). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jun 01, 2023)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000615355.3 First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024	Publications: PubMed (22) PubMed: 7813012‚ 14715275‚ 10732817‚ 15580564‚ 14749338‚ 15975577‚ 17635841‚ 26509018‚ 17049859‚ 10205265‚ 19050931‚ 11572858‚ 21584334‚ 10556301‚ 11078511‚ 23615451‚ 25144193‚ 27425821‚ 12374765‚ 25844556‚ 9590291‚ 10500148 Comment: Frequency data for this variant in the general population cannot be distinguished from that of the SMN2 gene, and is therefore uninformative in assessment of … (more) Frequency data for this variant in the general population 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 unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant causes reduced self-oligomerization, and reduced binding to Sm proteins (PMID: 9590291, 10500148). (less)
Likely pathogenic (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Werdnig-Hoffmann disease Affected status: no, yes Allele origin: paternal, unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000924369.1 First in ClinVar: Jun 23, 2019 Last updated: Jun 23, 2019	Publications: PubMed (3) PubMed: 7813012‚ 10732817‚ 15580564 Observation 1: Number of individuals with the variant: 1 Age: 0-9 years Sex: female Comment on evidence: 1 copy SMN1 and a clinical diagnosis of spinal muscular atrophy Type 1 Observation 2: Number of individuals with the variant: 1 Age: 20-29 years Sex: male Observation 3: Number of individuals with the variant: 1 Age: 30-39 years Sex: female
Pathogenic (Jan 13, 1995)	no assertion criteria provided Method: literature only	SPINAL MUSCULAR ATROPHY, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029958.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 26, 2017	Publications: PubMed (1) PubMed: 7813012 Comment on evidence: The first missense mutation discovered in the SMN1 gene in spinal muscular atrophy type I (253300) was a tyr272-to-cys (Y272C) mutation in exon 6, reported … (more) The first missense mutation discovered in the SMN1 gene in spinal muscular atrophy type I (253300) was a tyr272-to-cys (Y272C) mutation in exon 6, reported by Lefebvre et al. (1995). (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spinal muscular atrophy. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0501 - Missense variant is highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most common pathogenic variants reported in patients with spinal muscular atrophy (PMID: 7813012, 10205265, 10679938, 31301241). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Frequency data for this variant in the general population 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 unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant causes reduced self-oligomerization, and reduced binding to Sm proteins (PMID: 9590291, 10500148).

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Severe brain involvement in 5q spinal muscular atrophy type 0.	Mendonça RH	Annals of neurology	2019	PMID: 31301241
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
Tongue fasciculations in an infant with spinal muscular atrophy type 1.	Giannopoulou EZ	Clinical case reports	2015	PMID: 26509018
Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy.	Ripolone M	JAMA neurology	2015	PMID: 25844556
SMA-causing missense mutations in survival motor neuron (Smn) display a wide range of phenotypes when modeled in Drosophila.	Praveen K	PLoS genetics	2014	PMID: 25144193
The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein.	Kwon DY	Molecular biology of the cell	2013	PMID: 23615451
Multiplex digital PCR: breaking the one target per color barrier of quantitative PCR.	Zhong Q	Lab on a chip	2011	PMID: 21584334
Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene.	Alías L	Human genetics	2009	PMID: 19050931
Targeting of SMN to Cajal bodies is mediated by self-association.	Morse R	Human molecular genetics	2007	PMID: 17635841
Multiplex ligation-dependent probe amplification improves diagnostics in spinal muscular atrophy.	Arkblad EL	Neuromuscular disorders : NMD	2006	PMID: 17049859
A role for complexes of survival of motor neurons (SMN) protein with gemins and profilin in neurite-like cytoplasmic extensions of cultured nerve cells.	Sharma A	Experimental cell research	2005	PMID: 15975577
Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy.	Sun Y	Human mutation	2005	PMID: 15580564
Survival motor neuron (SMN) protein interacts with transcription corepressor mSin3A.	Zou J	The Journal of biological chemistry	2004	PMID: 14749338
Rpp20 interacts with SMN and is re-distributed into SMN granules in response to stress.	Hua Y	Biochemical and biophysical research communications	2004	PMID: 14715275
Involvement of survival motor neuron (SMN) protein in cell death.	Vyas S	Human molecular genetics	2002	PMID: 12374765
Characterization of functional domains of the SMN protein in vivo.	Wang J	The Journal of biological chemistry	2001	PMID: 11572858
Survival motor neuron protein modulates neuron-specific apoptosis.	Kerr DA	Proceedings of the National Academy of Sciences of the United States of America	2000	PMID: 11078511
An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA).	Wirth B	Human mutation	2000	PMID: 10679938
Detection of the survival motor neuron (SMN) genes by FISH: further evidence for a role for SMN2 in the modulation of disease severity in SMA patients.	Vitali T	Human molecular genetics	1999	PMID: 10556301
SMN mutants of spinal muscular atrophy patients are defective in binding to snRNP proteins.	Pellizzoni L	Proceedings of the National Academy of Sciences of the United States of America	1999	PMID: 10500148
Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling.	Wirth B	American journal of human genetics	1999	PMID: 10205265
SMN oligomerization defect correlates with spinal muscular atrophy severity.	Lorson CL	Nature genetics	1998	PMID: 9590291
Molecular diagnosis of non-deletion SMA patients using quantitative PCR of SMN exon 7.	Rochette CF	Neurogenetics	1997	PMID: 10732817
Identification and characterization of a spinal muscular atrophy-determining gene.	Lefebvre S	Cell	1995	PMID: 7813012
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Text-mined citations for rs104893922 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000344.4(SMN1):c.815A>G (p.Tyr272Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104893922 ...