NM_000023.4(SGCA):c.409G>A (p.Glu137Lys) AND Autosomal recessive limb-girdle muscular dystrophy type 2D

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Mar 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000341255.19

Allele description [Variation Report for NM_000023.4(SGCA):c.409G>A (p.Glu137Lys)]

NM_000023.4(SGCA):c.409G>A (p.Glu137Lys)

Gene:

SGCA:sarcoglycan alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.33

Genomic location:

Preferred name:

NM_000023.4(SGCA):c.409G>A (p.Glu137Lys)

HGVS:

NC_000017.11:g.50168397G>A
NG_008889.1:g.7393G>A
NM_000023.4:c.409G>AMANE SELECT
NM_001135697.3:c.409G>A
NP_000014.1:p.Glu137Lys
NP_001129169.1:p.Glu137Lys
LRG_203t1:c.409G>A
LRG_203:g.7393G>A
NC_000017.10:g.48245758G>A
NM_000023.2:c.409G>A
NR_135553.2:n.445G>A
Q16586:p.Glu137Lys

Protein change:

E137K

Links:

UniProtKB: Q16586#VAR_010416; dbSNP: rs372210292

NCBI 1000 Genomes Browser:

rs372210292

Molecular consequence:

NM_000023.4:c.409G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001135697.3:c.409G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_135553.2:n.445G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Autosomal recessive limb-girdle muscular dystrophy type 2D (LGMDR3)
Synonyms:: ADHALINOPATHY, PRIMARY; Limb-girdle muscular dystrophy, type 2D; Muscular dystrophy limb-girdle with alpha-sarcoglycan; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011968; MedGen: C2936332; Orphanet: 62; OMIM: 608099

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000649771	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9192266, 12075495, 19798725, 25214167, 26916285, 22095924, 28403181, 28492532
SCV000789139	Counsyl	no assertion criteria provided	Likely pathogenic (Jan 10, 2017)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22095924, 19798725, 9192266, 25214167, 18285821, 12075495, 16778590
SCV001367738	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001453379	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV003825579	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 26, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003931668	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004203165	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Precise Correction of Disease Mutations in Induced Pluripotent Stem Cells Derived From Patients With Limb Girdle Muscular Dystrophy.

Turan S, Farruggio AP, Srifa W, Day JW, Calos MP.

Mol Ther. 2016 Apr;24(4):685-96. doi: 10.1038/mt.2016.40. Epub 2016 Feb 26.

PubMed [citation]

PMID:: 26916285
PMCID:: PMC4886942

Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing.

Yu M, Zheng Y, Jin S, Gang Q, Wang Q, Yu P, Lv H, Zhang W, Yuan Y, Wang Z.

PLoS One. 2017;12(4):e0175343. doi: 10.1371/journal.pone.0175343.

PubMed [citation]

PMID:: 28403181
PMCID:: PMC5389788

See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000649771.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000789139.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001367738.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001453379.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003825579.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV003931668.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004203165.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 17, 2024

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