This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 137 of the SGCA protein (p.Glu137Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with limb-girdle muscular dystrophy (LGMD) (PMID: 9192266, 12075495, 19798725, 25214167, 26916285). ClinVar contains an entry for this variant (Variation ID: 286049). 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%. Experimental studies have shown that this missense change affects SGCA function (PMID: 22095924). This variant disrupts the p.Glu137 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been observed in individuals with SGCA-related conditions (PMID: 28403181), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000023.4(SGCA):c.409G>A (p.Glu137Lys)
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.
(9)
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
9
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.409G>A (p.Glu137Lys)
Variation ID: 286049 Accession: VCV000286049.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.33 17: 50168397 (GRCh38) [ NCBI UCSC ] 17: 48245758 (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 Dec 26, 2017 Jun 17, 2024 Mar 27, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000023.4:c.409G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000014.1:p.Glu137Lys missense NM_001135697.3:c.409G>A NP_001129169.1:p.Glu137Lys missense NR_135553.2:n.445G>A non-coding transcript variant NC_000017.11:g.50168397G>A NC_000017.10:g.48245758G>A NG_008889.1:g.7393G>A LRG_203:g.7393G>A LRG_203t1:c.409G>A Q16586:p.Glu137Lys - Protein change
- E137K
- Other names
- -
- Canonical SPDI
- NC_000017.11:50168396:G:A
-
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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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 (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2024 | RCV000341255.20 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 4, 2023 | RCV000725776.5 |
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
(Jul 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000339307.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
|
|
|
Pathogenic
(Jan 09, 2024)
|
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: SCV000649771.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 137 of the SGCA protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 137 of the SGCA protein (p.Glu137Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with limb-girdle muscular dystrophy (LGMD) (PMID: 9192266, 12075495, 19798725, 25214167, 26916285). ClinVar contains an entry for this variant (Variation ID: 286049). 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%. Experimental studies have shown that this missense change affects SGCA function (PMID: 22095924). This variant disrupts the p.Glu137 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been observed in individuals with SGCA-related conditions (PMID: 28403181), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2D
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367738.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3. This variant was detected in homozygous state.
|
|
|
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: SCV003931668.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
|
|
|
Pathogenic
(May 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004168957.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 34426522, 31589614, 22095924, 9192266, 30703231, 21031578, 30764848, 16778590, 31069529, 12075495, 18285821, 25214167, 31980526, 19798725, 26916285, 24077912, 30107846) (less)
|
|
|
Pathogenic
(May 26, 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: SCV003825579.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
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: SCV004203165.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Jan 10, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2D
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000789139.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Limb-girdle muscular dystrophy type 2D
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453379.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3. This variant was detected in homozygous state.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 34426522, 31589614, 22095924, 9192266, 30703231, 21031578, 30764848, 16778590, 31069529, 12075495, 18285821, 25214167, 31980526, 19798725, 26916285, 24077912, 30107846)
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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 137 of the SGCA protein (p.Glu137Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with limb-girdle muscular dystrophy (LGMD) (PMID: 9192266, 12075495, 19798725, 25214167, 26916285). ClinVar contains an entry for this variant (Variation ID: 286049). 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%. Experimental studies have shown that this missense change affects SGCA function (PMID: 22095924). This variant disrupts the p.Glu137 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been observed in individuals with SGCA-related conditions (PMID: 28403181), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3. This variant was detected in homozygous state.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 34426522, 31589614, 22095924, 9192266, 30703231, 21031578, 30764848, 16778590, 31069529, 12075495, 18285821, 25214167, 31980526, 19798725, 26916285, 24077912, 30107846)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing. | Yu M | PloS one | 2017 | PMID: 28403181 |
| Precise Correction of Disease Mutations in Induced Pluripotent Stem Cells Derived From Patients With Limb Girdle Muscular Dystrophy. | Turan S | Molecular therapy : the journal of the American Society of Gene Therapy | 2016 | PMID: 26916285 |
| MotorPlex provides accurate variant detection across large muscle genes both in single myopathic patients and in pools of DNA samples. | Savarese M | Acta neuropathologica communications | 2014 | PMID: 25214167 |
| Rescue of sarcoglycan mutations by inhibition of endoplasmic reticulum quality control is associated with minimal structural modifications. | Soheili T | Human mutation | 2012 | PMID: 22095924 |
| Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins. | Mendell JR | Annals of neurology | 2009 | PMID: 19798725 |
| Revised spectrum of mutations in sarcoglycanopathies. | Trabelsi M | European journal of human genetics : EJHG | 2008 | PMID: 18285821 |
| Sarcoglycanopathies: a multiplex molecular analysis for the most common mutations. | Gouveia TL | Diagnostic molecular pathology : the American journal of surgical pathology, part B | 2006 | PMID: 16778590 |
| Alpha-sarcoglycan deficiency featuring exercise intolerance and myoglobinuria. | Mongini T | Neuropediatrics | 2002 | PMID: 12075495 |
| 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 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SGCA | - | - | - | - |
Text-mined citations for rs372210292 ...
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 Sep 29, 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.