Variant: NM_213599.3(ANO5):c.172C>T (p.Arg58Trp)

CA202865

197402 (ClinVar)

Gene: ANO5

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 05785e65-0fb1-4b7f-85d7-691efc434976

Approved on: 2025-01-09

Published on: 2025-01-09

HGVS expressions

NM_213599.3:c.172C>T
NM_213599.3(ANO5):c.172C>T (p.Arg58Trp)
NC_000011.10:g.22218279C>T
CM000673.2:g.22218279C>T
NC_000011.9:g.22239825C>T
CM000673.1:g.22239825C>T
NC_000011.8:g.22196401C>T
NG_015844.1:g.30104C>T
ENST00000682084.1:n.3346C>T
ENST00000682266.1:c.-270-2818C>T
ENST00000682341.1:c.139-2818C>T
ENST00000682530.1:c.136-464C>T
ENST00000682684.1:n.560-2818C>T
ENST00000683197.1:c.139-2818C>T
ENST00000683411.1:c.-270-2818C>T
ENST00000683437.1:c.-270-2818C>T
ENST00000683834.1:n.381-2818C>T
ENST00000683897.1:n.425-2818C>T
ENST00000684365.1:n.550-2818C>T
ENST00000684663.1:c.136-2818C>T
ENST00000324559.9:c.172C>T
ENST00000648804.1:n.670-307C>T
ENST00000324559.8:c.172C>T
NM_001142649.1:c.169C>T
NM_213599.2:c.172C>T
NM_001142649.2:c.169C>T

Pathogenic

• Met criteria codes: PM3_Very Strong PP4 PP1

• Not Met criteria codes: PP3 PM5 PM2

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.172C>T variant in ANO5 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 58 (p.Arg58Trp). This variant has been detected in at least seven individuals with limb girdle muscular dystrophy, including in unknown phase with a pathogenic variant (c.191dup x2, 1.0 pts, PMID: 22499103, 30564623, LOVD Individual #00220701) and confirmed in trans with a pathogenic variant (c.2018A>G p.(Tyr673Cys), 1.0 pt, PMID: 23055322; c.148C>T p.(Arg50Ter), 1.0 pt, PMID: 30564623, LOVD Individual #00078872). Three individuals were homozygous for the variant (1.0 pt, PMID: 31353849, 27854218) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). The variant has also been reported to segregate with autosomal recessive LGMD in one affected family member (PP1; PMID: 23055322). The highest maximum allele frequency for this variant is 0.0004356 (15/34438 exome chromosomes) in the Admixed American population in gnomAD v2.1.1, which exceeds the LGMD VCEP threshold for PM2_Supporting (<0.0001) (criterion not met). The computational predictor REVEL gives a score of 0.572 (PP3, BP4 not met). 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 ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Very Strong, PP4, PP1.

Met criteria codes

• PM3_Very Strong: This variant has been detected in at least seven individuals with limb girdle muscular dystrophy, including in unknown phase with a pathogenic variant (c.191dup x2, 1.0 pts, PMID: 22499103, 30564623; LOVD Individual #00220701) and confirmed in trans with a pathogenic variant (c.2018A>G p.(Tyr673Cys), 1.0 pt, PMID: 23055322; c.148C>T p.(Arg50Ter), 1.0 pt, PMID: 30564623; LOVD Individual #00078872). Three individuals were homozygous for the variant (1.0 pt, PMID: 31353849, 27854218) (PM3_Very Strong).
• PP4: At least one patient with this variant displayed progressive muscle weakness, which is highly specific for autosomal recessive limb-girdle muscular dystrophy (PP4, PMID:32925086).
• PP1: The variant has been reported to segregate with autosomal recessive limb girdle muscular dystrophy in one affected family member (PP1; PMID: 23055322).

Not Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.572 (PP3, BP4 not met).
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: The highest maximum allele frequency for this variant is 0.0004356 (15/34438 exome chromosomes) in the Admixed American population in gnomAD v2.1.1, which exceeds the LGMD VCEP threshold for PM2_Supporting (<0.0001) (criterion not met).