Variant: NM_213599.3(ANO5):c.191dup (p.Asn64fs)

CA115378

2164 (ClinVar)

Gene: ANO5

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 013039c8-df1d-4c2d-b259-c75f9b6f9f5a

Approved on: 2025-01-09

Published on: 2025-01-09

HGVS expressions

NM_213599.3:c.191dupA
NM_213599.3:c.191dup
NM_213599.3(ANO5):c.191dup (p.Asn64fs)
NC_000011.10:g.22221107dup
CM000673.2:g.22221107dup
NC_000011.9:g.22242653dup
CM000673.1:g.22242653dup
NC_000011.8:g.22199229dup
NG_015844.1:g.32932dup
ENST00000682266.1:c.-260dup
ENST00000682341.1:c.149dup
ENST00000682530.1:c.*123dup
ENST00000682684.1:n.570dup
ENST00000683197.1:c.149dup
ENST00000683411.1:c.-260dup
ENST00000683437.1:c.-260dup
ENST00000683613.1:n.1185dup
ENST00000683834.1:n.391dup
ENST00000683897.1:n.435dup
ENST00000684365.1:n.560dup
ENST00000684663.1:c.146dup
ENST00000324559.9:c.191dup
ENST00000648804.1:n.756dup
ENST00000324559.8:c.191dup
NM_001142649.1:c.188dup
NM_213599.2:c.191dup
NM_001142649.2:c.188dup

Pathogenic

• Met criteria codes: PP4 PM3 PP1_Strong PVS1

• Not Met criteria codes: PM2 BS1

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.191dup (p.Asn64LysfsTer15) variant in ANO5 is a frameshift variant observed to cause a premature stop codon in biologically relevant exon 5/22, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1; PMID: 20096397). This variant has been detected in at least 26 individuals with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in at least eight patients (1.0 pt, PMID: 20096397, 28187523, 30919934; PM3). At least one patient with this variant displayed progressive proximal muscle weakness (PP4). The variant has also been reported to segregate with autosomal recessive LGMD in 4 affected family members from 3 families (PP1_Strong; PMID: 22336395, 20096397, 28187523). The filtering allele frequency of this variant is 0.001770 (the lower threshold of the 95% CI of 139/67894 genome chromosomes) in the European (non-Finnish) population in gnomAD v3.1.2, which is higher than the LGMD VCEP threshold (>0.002) for BS1; however, this variant is a frequently observed variant among affected patients and the VCEP opted not to apply this code (BS1 exception). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PP1_Strong.

Met criteria codes

• PP4: At least one patient with this variant displayed proximal muscle weakness which is highly specific for autosomal recessive limb-girdle muscular dystrophy (PP4, PMID: 22336395, 22499103, 20096397, 30919934).
• PM3: This variant has been detected in at least 26 individuals with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in at least eight patients (1.0 pt, PMID: 20096397, 28187523, 30919934; PM3).
• PP1_Strong: The variant has been reported to segregate with autosomal recessive LGMD in 4 affected family members from 3 families (PP1_Strong; PMID: 22336395, 20096397, 28187523).
• PVS1: The c.191dup p.(Asn64LysfsTer15) variant in ANO5 is a frameshift variant observed to cause a premature stop codon in biologically relevant exon 5/22, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1; PMID: 20096397).

Not Met criteria codes

• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: The filtering allele frequency of this variant is 0.001770 (the lower threshold of the 95% CI of 139/67894 genome chromosomes) in the European (non-Finnish) population in gnomAD v3.1.2, which is higher than the LGMD VCEP threshold (>0.002) for BS1; however, this variant is a frequently observed variant among affected patients and the VCEP opted not to apply this code (BS1 exception).