This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 34 of the SGCA protein (p.Arg34Cys). This variant is present in population databases (rs758647756, gnomAD 0.0009%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9192266, 21031578, 27906075, 32528171). ClinVar contains an entry for this variant (Variation ID: 217250). 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 SGCA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg34 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7663524, 9032047, 26944168). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000023.4(SGCA):c.100C>T (p.Arg34Cys)
Germline
Classification
Help
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.
(7)
Help
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000023.4(SGCA):c.100C>T (p.Arg34Cys)
Variation ID: 217250 Accession: VCV000217250.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.33 17: 50167430 (GRCh38) [ NCBI UCSC ] 17: 48244791 (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 Oct 19, 2015 Sep 29, 2024 Apr 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000023.4:c.100C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000014.1:p.Arg34Cys missense NM_001135697.3:c.100C>T NP_001129169.1:p.Arg34Cys missense NR_135553.2:n.136C>T non-coding transcript variant NC_000017.11:g.50167430C>T NC_000017.10:g.48244791C>T NG_008889.1:g.6426C>T LRG_203:g.6426C>T LRG_203t1:c.100C>T Q16586:p.Arg34Cys - Protein change
- R34C
- Other names
- -
- Canonical SPDI
- NC_000017.11:50167429:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| SGCA | - | - |
GRCh38 GRCh37 |
746 | 771 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2024 | RCV000201165.13 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 16, 2024 | RCV000493338.5 |
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
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
(Dec 31, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
Limb-girdle muscular dystrophy, type 2D
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000255836.2
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
|
|
|
Pathogenic
(Dec 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2D
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002228803.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 34 of the SGCA protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 34 of the SGCA protein (p.Arg34Cys). This variant is present in population databases (rs758647756, gnomAD 0.0009%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9192266, 21031578, 27906075, 32528171). ClinVar contains an entry for this variant (Variation ID: 217250). 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 SGCA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg34 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7663524, 9032047, 26944168). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Apr 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000581759.5
First in ClinVar: Jul 02, 2017 Last updated: Sep 29, 2024 |
Comment:
Observed in apparent homozygous state or in the presence of a second SGCA pathogenic variant, phase unknown, in patients with SGCA-related limb-girdle muscular dystrophy in … (more)
Observed in apparent homozygous state or in the presence of a second SGCA pathogenic variant, phase unknown, in patients with SGCA-related limb-girdle muscular dystrophy in the literature and not observed in homozygous state in controls (PMID: 9192266, 9153448, 27906075, Lekshmi_2022_CaseReport); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9153448, 19781108, 9192266, 26944168, Lekshmi2022[casereport], 30564623, 21031578, 27906075, 32528171) (less)
|
|
|
Likely pathogenic
(Feb 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2D
Affected status: unknown
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV003931629.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
|
|
|
Pathogenic
(Jul 20, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000332844.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 02, 2017 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2D
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004203158.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2D
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020087.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
Comment:
Comment:
Observed in apparent homozygous state or in the presence of a second SGCA pathogenic variant, phase unknown, in patients with SGCA-related limb-girdle muscular dystrophy in the literature and not observed in homozygous state in controls (PMID: 9192266, 9153448, 27906075, Lekshmi_2022_CaseReport); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9153448, 19781108, 9192266, 26944168, Lekshmi2022[casereport], 30564623, 21031578, 27906075, 32528171)
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:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 34 of the SGCA protein (p.Arg34Cys). This variant is present in population databases (rs758647756, gnomAD 0.0009%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9192266, 21031578, 27906075, 32528171). ClinVar contains an entry for this variant (Variation ID: 217250). 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 SGCA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg34 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7663524, 9032047, 26944168). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Observed in apparent homozygous state or in the presence of a second SGCA pathogenic variant, phase unknown, in patients with SGCA-related limb-girdle muscular dystrophy in the literature and not observed in homozygous state in controls (PMID: 9192266, 9153448, 27906075, Lekshmi_2022_CaseReport); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9153448, 19781108, 9192266, 26944168, Lekshmi2022[casereport], 30564623, 21031578, 27906075, 32528171)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. | Töpf A | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32528171 |
| Nuclear bodies reorganize during myogenesis in vitro and are differentially disrupted by expression of FSHD-associated DUX4. | Homma S | Skeletal muscle | 2016 | PMID: 27906075 |
| Probable high prevalence of limb-girdle muscular dystrophy type 2D in Taiwan. | Liang WC | Journal of the neurological sciences | 2016 | PMID: 26944168 |
| Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. | Mendell JR | Annals of neurology | 2010 | PMID: 21031578 |
| Mutational diversity and hot spots in the alpha-sarcoglycan gene in autosomal recessive muscular dystrophy (LGMD2D). | Carrié A | Journal of medical genetics | 1997 | PMID: 9192266 |
| Primary adhalinopathy (alpha-sarcoglycanopathy): clinical, pathologic, and genetic correlation in 20 patients with autosomal recessive muscular dystrophy. | Eymard B | Neurology | 1997 | PMID: 9153448 |
| Mutations in the sarcoglycan genes in patients with myopathy. | Duggan DJ | The New England journal of medicine | 1997 | PMID: 9032047 |
| Primary adhalinopathy: a common cause of autosomal recessive muscular dystrophy of variable severity. | Piccolo F | Nature genetics | 1995 | PMID: 7663524 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SGCA | - | - | - | - |
Text-mined citations for rs758647756 ...
HelpThese 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 Oct 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.