Variant: NM_213599.3(ANO5):c.2272C>T (p.Arg758Cys)

CA130516

2166 (ClinVar)

Gene: ANO5

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: fbaa9261-0755-4e95-80b7-9e2d4a82b2ed

Approved on: 2025-01-07

Published on: 2025-01-07

HGVS expressions

NM_213599.3:c.2272C>T
NM_213599.3(ANO5):c.2272C>T (p.Arg758Cys)
NC_000011.10:g.22274605C>T
CM000673.2:g.22274605C>T
NC_000011.9:g.22296151C>T
CM000673.1:g.22296151C>T
NC_000011.8:g.22252727C>T
NG_015844.1:g.86430C>T
ENST00000532043.2:n.289C>T
ENST00000682266.1:c.1822C>T
ENST00000682341.1:c.2230C>T
ENST00000683197.1:c.2230C>T
ENST00000683411.1:c.1822C>T
ENST00000683437.1:c.1822C>T
ENST00000683613.1:n.3266C>T
ENST00000684663.1:c.2227C>T
ENST00000324559.9:c.2272C>T
ENST00000648804.1:n.2607C>T
ENST00000324559.8:c.2272C>T
ENST00000532043.1:n.289C>T
NM_001142649.1:c.2269C>T
NM_213599.2:c.2272C>T
NM_001142649.2:c.2269C>T

Pathogenic

• Met criteria codes: PM3_Very Strong PP4 PP3 PP1_Strong

• Not Met criteria codes: PVS1 BS2 BS3 BS1 BS4 BP3 BP2 BP4 BP1 BP5 BP7 PS4 PS3 PS2 PS1 BA1 PP2 PM1 PM5 PM4 PM6 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.2272C>T variant in ANO5 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 758 (p.Arg758Cys). This variant has been detected in at least 7 individuals with LGMD, five of whom had a second ANO5 variant classified as pathogenic or likely pathogenic, with one confirmed in trans by parental testing (c.191dup x5, 3.0 pts, PMID: 25135358, 24803842, 21739273, 21186264). Two patients were homozygous for the variant (1.0 pt, PMID: 20096397) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4; PMD: 31395899). The variant has been reported to segregate with LGMD in six affected family members from three families (PP1_Strong; PMID: 20096397, 27911336). The maximum minor allele frequency for this variant is 0.0003116 (40/128354 chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which exceeds the VCEP threshold of 0.0001 for PM2 (criterion not met). The computational predictor REVEL gives a score of 0.82, which meets the VCEP threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3). 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; 01/07/2025): PM3_Very Strong, PP4, PP1_Strong, PP3.

Met criteria codes

• PM3_Very Strong: This variant has been detected in at least 7 individuals with LGMD 2L. Of those individuals, 5 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 1 of those were confirmed in trans by parental testing (c.191dup x5, 3.0pt, PMIDs: 25135358, 24803842, 21739273, 21186264). 2 individuals were homozygous for the variant (1.0pt, PMID: 20096397) (PM3_VeryStrong).
• PP4: At least one patient with this variant displayed progressive weakness, which is specific for LGMD 2L (PP4_supporting, PMID: 31395899).
• PP3: The computational predictor REVEL gives a score of 0.82, which meets the threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3).
• PP1_Strong: The variant has been reported to segregate with LGMD 2L in 6 affected family members from 3 families (PP1_Strong; PMID: 20096397, 27911336).

Not Met criteria codes

• 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
• 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
• BS4: 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
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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
• BP7: 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
• PS3: 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
• 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
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: c.2273G>A [ p.Arg758His ] = UNCERTAIN SIGNIFICANCE
• PM4: 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: European (non-Finnish) calculated = 0.00631 --> 0.0063 [[ CODE CAN'T BE MET ]]