Published functional studies demonstrate that the I124T variant disrupts the membrane localization of the protein (PMID: 31061434); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10993494, 30919934, 22095924, 9032047, 18996010, 14595658, 11121445, 9192266, 24742800, 21031578, 30564623, 19781108, 31061434, 19798725)
ClinVar Genomic variation as it relates to human health
NM_000023.4(SGCA):c.371T>C (p.Ile124Thr)
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.
(11)
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
11
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.371T>C (p.Ile124Thr)
Variation ID: 188733 Accession: VCV000188733.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.33 17: 50168005 (GRCh38) [ NCBI UCSC ] 17: 48245366 (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 Mar 29, 2015 Jun 17, 2024 Jan 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000023.4:c.371T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000014.1:p.Ile124Thr missense NM_001135697.3:c.371T>C NP_001129169.1:p.Ile124Thr missense NR_135553.2:n.407T>C non-coding transcript variant NC_000017.11:g.50168005T>C NC_000017.10:g.48245366T>C NG_008889.1:g.7001T>C LRG_203:g.7001T>C LRG_203t1:c.371T>C Q16586:p.Ile124Thr - Protein change
- I124T
- Other names
- -
- Canonical SPDI
- NC_000017.11:50168004:T:C
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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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Exome Aggregation Consortium (ExAC) 0.00002
- 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 (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 25, 2024 | RCV000169036.28 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 21, 2023 | RCV000724041.7 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Apr 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000229992.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 6
Sex: mixed
|
|
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Likely pathogenic
(Mar 29, 2014)
|
criteria provided, single submitter
Method: literature only
|
Limb-girdle muscular dystrophy, type 2D
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220189.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448138.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hypotonia (present) , Motor delay (present) , Myopathy (present) , Short stature (present) , Abnormal circulating creatine kinase concentration (present)
Sex: female
|
|
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Pathogenic
(Mar 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2D
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002776140.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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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: SCV003931663.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
|
|
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Pathogenic
(Aug 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004031012.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Comment:
Published functional studies demonstrate that the I124T variant disrupts the membrane localization of the protein (PMID: 31061434); Not observed at a significant frequency in large … (more)
Published functional studies demonstrate that the I124T variant disrupts the membrane localization of the protein (PMID: 31061434); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10993494, 30919934, 22095924, 9032047, 18996010, 14595658, 11121445, 9192266, 24742800, 21031578, 30564623, 19781108, 31061434, 19798725) (less)
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2D
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048273.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The c.371T>C (p.Ile124Thr) variant in SGCA gene has been reported in combination with another SGCA variant in multiple individuals and families affected with limb girdle … (more)
The c.371T>C (p.Ile124Thr) variant in SGCA gene has been reported in combination with another SGCA variant in multiple individuals and families affected with limb girdle muscular dystrophy (Fischer et al., 2003; Klinge et al., 2008). Experimental studies have shown that this missense change impairs proper localization of the SGCA protein (Soheili et al., 2012). The p.Ile124Thr variant is reported with the allele frequency (0.002%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Ile at position 124 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ile124Thr in SGCA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Fatigable weakness (present) , Delayed speech and language development (present) , Calf muscle hypertrophy (present)
|
|
|
Pathogenic
(Apr 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: SCV002020092.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Jan 02, 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: SCV000830955.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 124 of the SGCA protein (p.Ile124Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 124 of the SGCA protein (p.Ile124Thr). This variant is present in population databases (rs768814872, gnomAD 0.009%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9032047, 10993494, 14595658, 18996010, 19798725). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188733). 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). For these reasons, this variant has been classified as Pathogenic. (less)
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|
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Pathogenic
(Jan 25, 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: SCV004203155.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Aug 03, 2020)
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no assertion criteria provided
Method: clinical testing
|
Limb-girdle muscular dystrophy type 2D
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002087564.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Comment:
Comment:
The c.371T>C (p.Ile124Thr) variant in SGCA gene has been reported in combination with another SGCA variant in multiple individuals and families affected with limb girdle muscular dystrophy (Fischer et al., 2003; Klinge et al., 2008). Experimental studies have shown that this missense change impairs proper localization of the SGCA protein (Soheili et al., 2012). The p.Ile124Thr variant is reported with the allele frequency (0.002%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Ile at position 124 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ile124Thr in SGCA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 124 of the SGCA protein (p.Ile124Thr). This variant is present in population databases (rs768814872, gnomAD 0.009%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9032047, 10993494, 14595658, 18996010, 19798725). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188733). 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). For these reasons, this variant has been classified as Pathogenic.
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:
Published functional studies demonstrate that the I124T variant disrupts the membrane localization of the protein (PMID: 31061434); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10993494, 30919934, 22095924, 9032047, 18996010, 14595658, 11121445, 9192266, 24742800, 21031578, 30564623, 19781108, 31061434, 19798725)
Comment:
The c.371T>C (p.Ile124Thr) variant in SGCA gene has been reported in combination with another SGCA variant in multiple individuals and families affected with limb girdle muscular dystrophy (Fischer et al., 2003; Klinge et al., 2008). Experimental studies have shown that this missense change impairs proper localization of the SGCA protein (Soheili et al., 2012). The p.Ile124Thr variant is reported with the allele frequency (0.002%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Ile at position 124 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ile124Thr in SGCA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 124 of the SGCA protein (p.Ile124Thr). This variant is present in population databases (rs768814872, gnomAD 0.009%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9032047, 10993494, 14595658, 18996010, 19798725). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188733). 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). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Sarcoglycanopathies: can muscle immunoanalysis predict the genotype? | Klinge L | Neuromuscular disorders : NMD | 2008 | PMID: 18996010 |
| On symptomatic heterozygous alpha-sarcoglycan gene mutation carriers. | Fischer D | Annals of neurology | 2003 | PMID: 14595658 |
| Expression profiling in the muscular dystrophies: identification of novel aspects of molecular pathophysiology. | Chen YW | The Journal of cell biology | 2000 | PMID: 11121445 |
| Sarcoglycanopathies in Dutch patients with autosomal recessive limb girdle muscular dystrophy. | Ginjaar HB | Journal of neurology | 2000 | PMID: 10993494 |
| 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 |
| Mutations in the sarcoglycan genes in patients with myopathy. | Duggan DJ | The New England journal of medicine | 1997 | PMID: 9032047 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SGCA | - | - | - | - |
Text-mined citations for rs768814872 ...
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.