Variant: NM_000023.4(SGCA):c.700G>A (p.Asp234Asn)

CA246512

198031 (ClinVar)

Gene: SGCA

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 3c873079-f7a8-4078-bc51-56af80495f40

Approved on: 2025-01-07

Published on: 2025-01-07

HGVS expressions

NM_000023.4:c.700G>A
NM_000023.4(SGCA):c.700G>A (p.Asp234Asn)
NC_000017.11:g.50169207G>A
CM000679.2:g.50169207G>A
NC_000017.10:g.48246568G>A
CM000679.1:g.48246568G>A
NC_000017.9:g.45601567G>A
NG_008889.1:g.8203G>A
ENST00000504073.2:c.597+103G>A
ENST00000511303.6:n.309+635G>A
ENST00000512526.2:c.575+635G>A
ENST00000682109.1:c.580G>A
ENST00000683226.1:n.410G>A
ENST00000683294.1:c.700G>A
ENST00000262018.8:c.700G>A
ENST00000262018.7:c.700G>A
ENST00000344627.10:c.584+635G>A
ENST00000502555.5:c.*359G>A
ENST00000504073.1:c.64+103G>A
ENST00000511303.5:c.305+635G>A
ENST00000512526.1:c.419+635G>A
ENST00000513821.5:c.700G>A
ENST00000513942.5:n.375+635G>A
NM_000023.2:c.700G>A
NM_001135697.1:c.584+635G>A
NM_000023.3:c.700G>A
NM_001135697.2:c.584+635G>A
NR_135553.1:n.756G>A
NM_001135697.3:c.584+635G>A
NR_135553.2:n.736G>A

Likely Pathogenic

• Met criteria codes: PM3 PP4_Strong

• Not Met criteria codes: PP1 PP3 PP2 PM6 PM2 PM1 PM5 PM4 PVS1 BS2 BS4 BS3 BS1 BP2 BP4 BP1 BP3 BP5 BP7 BA1 PS2 PS4 PS1

Expert Panel

Limb Girdle Muscular Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SGCA Version 1.0.0

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_000023.4: c.700G>A variant in SGCA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 234 (p.Asp234Asn). This variant has been detected in at least three individuals with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pt, ClinVar SCV000769867.5 internal data communication) and in unknown phase with a variant classified as at least likely pathogenic (c.100C>T (p.Arg34Cys), 0.25 pts, Washington University internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of alpha-sarcoglycan protein in skeletal muscle, which is highly specific for SGCA-related LGMD (PP4_Strong, Washington University internal clinic data communication). The highest minor allele frequency of this variant is 0.0005498 (19/34560 exome chromosomes) in the Admixed American population in gnomAD v2.1.1 (PM2_Supporting, BS1 not met). The computational predictor REVEL gives a score of 0.491 (BP4, PP3 not met). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025)(LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3, PP4_Strong.

Met criteria codes

• PM3: This variant has been detected in 3 individuals with autosomal recessive limb-girdle muscular dystrophy. One individual was compound heterozygous for another variant which has been curated to be likely pathogenic and confirmed in trans by family testing. 2 individuals were homozygous for the variant (2.0pt total, Personal contact of Dr. Weihl, SCV000769867.5) (PM3_Strong). ARC: phase not confirmed in GRASP-LGMD case (downgrade to PM3)
• PP4_Strong: At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of alpha-sarcoglycan protein in skeletal muscle, which is highly specific for SGCA-related LGMD (PP4_Strong, Personal Contact of Dr. Weihl).

Not Met criteria codes

• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: 0.491 vs. ≥0.70 (REVEL)
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: The greatest minor allele frequency of this variant is 0.0005498 (19/34560 exome chromosomes) in the Admixed American population in gnomAD v2.1.1 (PM2, BS1 not met).
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00055 (19/34560 alleles)
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: 0.491 vs. ≤0.10 (REVEL) AND 0.05 vs. 0.00 (SpliceAI)
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline