Variant: NM_213599.3(ANO5):c.139-1del

CA10605474

286467 (ClinVar)

Gene: ANO5

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 7096a7c3-a0bc-4703-98dd-9fcfd14fc795

Approved on: 2025-01-07

Published on: 2025-01-07

HGVS expressions

NM_213599.3:c.139-1del
NM_213599.3(ANO5):c.139-1del
NC_000011.10:g.22218245del
CM000673.2:g.22218245del
NC_000011.9:g.22239791del
CM000673.1:g.22239791del
NC_000011.8:g.22196367del
NG_015844.1:g.30070del
ENST00000682084.1:n.3313-1del
ENST00000682266.1:c.-270-2852del
ENST00000682341.1:c.139-2852del
ENST00000682530.1:c.136-498del
ENST00000682684.1:n.560-2852del
ENST00000683197.1:c.139-2852del
ENST00000683411.1:c.-270-2852del
ENST00000683437.1:c.-270-2852del
ENST00000683834.1:n.381-2852del
ENST00000683897.1:n.425-2852del
ENST00000684365.1:n.550-2852del
ENST00000684663.1:c.136-2852del
ENST00000324559.9:c.139-1del
ENST00000648804.1:n.670-341del
ENST00000324559.8:c.139-1del
NM_001142649.1:c.136-1del
NM_213599.2:c.139-1del
NM_001142649.2:c.136-1del

Uncertain Significance

• Met criteria codes: PVS1_Moderate PM2_Supporting

• Not Met criteria codes: BS3 BS1 BP3 BP4 BP1 BP5 PS3 PS1 BA1 PM3 PM1 PM4 PM5 PP3 PP2

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 ANO5 Version 1.0.0

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_213599.3: c.139-1del variant in ANO5 occurs within the canonical splice acceptor site (-1, -2 dinucleotide) of intron 3. It is predicted to cause skipping of biologically relevant exon 4/22, resulting in an in-frame deletion of exon 4 (42 amino acids) and premature truncation of <10% the protein (PVS1_Moderate). This variant has been observed in the heterozygous state in at least five individuals with a clinical suspicion of LGMD, but no other variants in ANO5 were identified in these individuals (PMID: 30564623; ClinVar SCV000570206.4 internal data communication, ClinVar SCV000933284.6 internal data communication) (PM3 not met). The filtering allele frequency of this variant is 0.000031407 (the upper threshold of the 95% CI of 25/1111726 exome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold ≤0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, due to the limited evidence available, this variant is classified as a variant of uncertain significance 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): PVS1_Moderate, PM2_Supporting.

Met criteria codes

• PVS1_Moderate: The c.139-1del variant in ANO5 occurs within the canonical splice acceptor site (-1) of intron 3. It is predicted to cause skipping of biologically-relevant-exon 4/22, resulting in the in-frame deletion of exon 4 (42 amino acids), resulting in a truncated protein. PVS1 is applied at the Moderate strength based on the loss of <10% of the protein length.
• PM2_Supporting: The filtering allele frequency of this variant is 0.000031407 (the upper threshold of the 95% CI of 25/1111726 exome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold ≤0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting).

Not Met criteria codes

• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: 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
• BP4: The c.139-1del variant is an intronic variant that affects the canonical splice site; PVS1 considered instead.
• BP1: 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
• PS3: 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
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: This variant has been observed in the heterozygous state in at least five individuals with a clinical suspicion of LGMD, but no other variants in ANO5 were identified in these individuals (PMID: 30564623; ClinVar SCV000570206.4, SCV000933284.6) (PM3 not met).
• PM1: 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
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline