Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_213599.3(ANO5):c.692G>T (p.Gly231Val)

CA224418

2165 (ClinVar)

Gene: ANO5 (HGNC:203859)
Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)
Inheritance Mode: Autosomal recessive inheritance
UUID: 7d577c8a-190f-4025-9e0f-f0496b2ecdd5
Approved on: 2026-02-24
Published on: 2026-04-09

HGVS expressions

NM_213599.3:c.692G>T
NM_213599.3(ANO5):c.692G>T (p.Gly231Val)
NC_000011.10:g.22236206G>T
CM000673.2:g.22236206G>T
NC_000011.9:g.22257752G>T
CM000673.1:g.22257752G>T
NC_000011.8:g.22214328G>T
NG_015844.1:g.48031G>T
ENST00000682266.1:c.242G>T
ENST00000682341.1:c.650G>T
ENST00000682530.1:c.*624G>T
ENST00000682684.1:n.1071G>T
ENST00000683197.1:c.650G>T
ENST00000683411.1:c.242G>T
ENST00000683437.1:c.242G>T
ENST00000683613.1:n.1686G>T
ENST00000683834.1:n.892G>T
ENST00000684663.1:c.647G>T
ENST00000324559.9:c.692G>T
ENST00000648804.1:n.1213+8620G>T
ENST00000324559.8:c.692G>T
NM_001142649.1:c.689G>T
NM_213599.2:c.692G>T
NM_001142649.2:c.689G>T
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Likely Pathogenic

Met criteria codes 2
PP4 PM3_Very Strong
Not Met criteria codes 5
PP3 PM5 PM2 BS1 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ANO5 Version 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Limb Girdle Muscular Dystrophy VCEP
The NM_213599.3: c.692G>T variant in ANO5 is a missense variant expected to result in the substitution of glycine for valine at amino acid 231, p.(Gly231Val). The Grpmax FAF for this variant is 0.002635 in gnomAD v4.1.0, which is greater than the VCEP threshold of 0.001 for BS1. However, this variant is recognized as one of the most common pathogenic variants in ANO5, and the VCEP opted not to apply this code (BS1 exception). The Total population also includes four homozygous individuals, but variants in ANO5 can be associated with mild and late onset disease, and the VCEP does not consider this evidence contradictory with the pathogenicity of this variant. Across a selection of the available data, this variant has been identified in over 20 individuals with features consistent with LGMD (PMID: 34008892, 36575883, 25891276, 32925086, 35628876, 31353849; LOVD ANO5_000005; GRASP-LGMD Consortium internal data communication). These observations include eight unrelated patients in whom it was reported in unconfirmed phase with a pathogenic variant (c.191dup p.(Asn64LysfsTer15) x6, 3.0 pts, PMID: 35628876, 31353849, GRASP-LGMD Consortium internal data communication; c.1898+1G>A, 0.5 pts, GRASP-LGMD Consortium internal data communication; c.2272C>T p.(Arg758Cys), 0.5 pts, GRASP-LGMD Consortium internal data communication) (PM3_Very Strong). This variant has also been reported in a homozygous state in at least four unrelated patients experiencing muscle weakness and with signs of atrophy or dystrophy on muscle biopsy (PMID: 25891276, 31353849). At least one patient with this variant and a second presumed diagnostic ANO5 allele exhibited limb girdle muscle weakness and had a clinical diagnosis of LGMD (PP4). The computational predictor REVEL gives a score of 0.49 (PP3, BP4 not met). In summary, this variant is 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 (specifications version 2.0.0, 02/24/2026): PM3_Very Strong, PP4.
Met criteria codes
PP4
At least one patient with this variant and a second presumed diagnostic ANO5 allele exhibited limb girdle muscle weakness and had a clinical diagnosis of LGMD (PP4).
PM3_Very Strong
Across a selection of the available data, this variant has been identified in over 20 individuals with features consistent with LGMD (PMID: 34008892, 36575883, 25891276, 32925086, 35628876, 31353849; LOVD ANO5_000005; GRASP-LGMD Consortium internal data communication). These observations include eight unrelated patients in whom it was reported in unconfirmed phase with a pathogenic variant (c.191dup p.(Asn64LysfsTer15) x6, 3.0 pts, PMID: 35628876, 31353849, GRASP-LGMD Consortium internal data communication; c.1898+1G>A, 0.5 pts, GRASP-LGMD Consortium internal data communication; c.2272C>T p.(Arg758Cys), 0.5 pts, GRASP-LGMD Consortium internal data communication). This variant has also been reported in a homozygous state in at least four unrelated patients experiencing muscle weakness and with signs of atrophy or dystrophy on muscle biopsy (PMID: 25891276, 31353849). (PM3_Very Strong) scored: c.191dup x6: 3 pt, predicted on different haplotypes c.1898+1G>A: 0.5 pt, predicted on different haplotypes c.2272C>T p.(Arg758Cys): 0.5 pt, predicted on different haplotypes symptomatic hom x4 unscored: c.2478G>T p.(Trp826Cys) (VUS) c.1359G>C p.(Tyr453Ter) x2 c.2498T>A p.(Met833Lys) c.2342T>C p.(Leu781Pro) c.40G>A p.(Gly14Arg) c.709A>G p.(Ile237Val), confirmed in trans LOVD ANO5_000005: 49 reported entries
Not Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.49 (PP3, BP4 not met). SpliceAI 0.15
PM5
no other missense variants seem to have been reported at this position
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is 0.002635, which is greater than the VCEP threshold of 0.001 for BS1. However, this variant is recognized as one of the most common pathogenic variants in ANO5, and the VCEP opted not to apply this code (BS1 exception). 4 homozygotes in Total population: 1 65-70, 1 40-45
BP4
The computational predictor REVEL gives a score of 0.49 (PP3, BP4 not met). SpliceAI 0.15
Curation History
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