NM_000023.4(SGCA):c.409G>C (p.Glu137Gln) AND Autosomal recessive limb-girdle muscular dystrophy type 2D

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Feb 26, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000670049.20

Allele description [Variation Report for NM_000023.4(SGCA):c.409G>C (p.Glu137Gln)]

NM_000023.4(SGCA):c.409G>C (p.Glu137Gln)

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>C (p.Glu137Gln)

Other names:

p.Glu137Gln

HGVS:

NC_000017.11:g.50168397G>C
NG_008889.1:g.7393G>C
NM_000023.4:c.409G>CMANE SELECT
NM_001135697.3:c.409G>C
NP_000014.1:p.Glu137Gln
NP_001129169.1:p.Glu137Gln
LRG_203t1:c.409G>C
LRG_203:g.7393G>C
NC_000017.10:g.48245758G>C
NM_000023.2:c.409G>C
NM_000023.3:c.409G>C
NR_135553.2:n.445G>C

Protein change:

E137Q

Links:

dbSNP: rs372210292

NCBI 1000 Genomes Browser:

rs372210292

Molecular consequence:

NM_000023.4:c.409G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001135697.3:c.409G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_135553.2:n.445G>C - 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

Recent activity

Clear Turn Off Turn On

poglut1 [Cyclopterus lumpus]
poglut1 [Cyclopterus lumpus]
Gene ID:117743228

Gene

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001211376	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 8, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 28403181, 30703231, 9192266, 12075495, 19798725, 22095924, 25214167, 26916285, 28492532
SCV001453380	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002019192	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 24, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060335	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Oct 1, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30703231, 28403181 Citation Link,
SCV004013489	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28403181, 9192266, 25741868
SCV004203152	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 26, 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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	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

Citations

PubMed

Alpha-sarcoglycan deficiency featuring exercise intolerance and myoglobinuria.

Mongini T, Doriguzzi C, Bosone I, Chiadò-Piat L, Hoffman EP, Palmucci L.

Neuropediatrics. 2002 Apr;33(2):109-11.

PubMed [citation]

PMID:: 12075495

Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins.

Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, Kota J, Coley BD, Galloway G, Craenen JM, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Viollet L, Walker CM, Sahenk Z, Clark KR.

Ann Neurol. 2009 Sep;66(3):290-7. doi: 10.1002/ana.21732.

PubMed [citation]

PMID:: 19798725
PMCID:: PMC6014624

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001211376.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 137 of the SGCA protein (p.Glu137Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SGCA-related conditions (PMID: 28403181, 30703231). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554420). 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.Glu137 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9192266, 12075495, 19798725, 22095924, 25214167, 26916285). 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.

#	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 Natera, Inc., SCV001453380.1

#	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, SCV002019192.3

#	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 Myriad Genetics, Inc., SCV002060335.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

NM_000023.2(SGCA):c.409G>C(E137Q) is a missense variant classified as a variant of uncertain significance in the context of alpha-sarcoglycanopathy. E137Q has been observed in cases with relevant disease (PMID: 28403181, 30703231). Functional assessments of this variant are not available in the literature. E137Q has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_000023.2(SGCA):c.409G>C(E137Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

#	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 3billion, SCV004013489.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SGCA related disorder (ClinVar ID: VCV000554420 / PMID: 28403181). Different missense changes at the same codon (p.Glu137Gly, p.Glu137Lys) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009438, VCV000286049 / PMID: 9192266). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

#	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		1	not provided	not provided	not provided

From Baylor Genetics, SCV004203152.2

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine