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.2018A>G (p.Tyr673Cys)

CA232789

140555 (ClinVar)

Gene: ANO5
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
UUID: 1011713c-b155-4165-9bec-be5fdb84e664
Approved on: 2025-01-07
Published on: 2025-01-07

HGVS expressions

NM_213599.3:c.2018A>G
NM_213599.3(ANO5):c.2018A>G (p.Tyr673Cys)
NC_000011.10:g.22270431A>G
CM000673.2:g.22270431A>G
NC_000011.9:g.22291977A>G
CM000673.1:g.22291977A>G
NC_000011.8:g.22248553A>G
NG_015844.1:g.82256A>G
ENST00000532043.2:n.35A>G
ENST00000682266.1:c.1568A>G
ENST00000682341.1:c.1976A>G
ENST00000683197.1:c.1976A>G
ENST00000683411.1:c.1568A>G
ENST00000683437.1:c.1568A>G
ENST00000683613.1:n.3012A>G
ENST00000684663.1:c.1973A>G
ENST00000324559.9:c.2018A>G
ENST00000648804.1:n.2353A>G
ENST00000324559.8:c.2018A>G
ENST00000532043.1:n.35A>G
NM_001142649.1:c.2015A>G
NM_213599.2:c.2018A>G
NM_001142649.2:c.2015A>G
More

Pathogenic

Met criteria codes 5
PM2_Supporting PM3_Strong PP4 PP3 PP1_Strong
Not Met criteria codes 21
BS4 BS3 BS1 BS2 PVS1 BP5 BP7 BP2 BP4 BP1 BP3 PS2 PS4 PS3 PS1 PM1 PM5 PM4 PM6 BA1 PP2

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 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Limb Girdle Muscular Dystrophy VCEP
The NM_213599.3: c.2018A>G variant in ANO5 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 673 (p.Tyr673Cys). This variant has been detected in at least 6 individuals with autosomal recessive limb-girdle muscular dystrophy. Of those individuals, five had another pathogenic or likely pathogenic variant, with three confirmed in trans by parental testing (c.191dup x2, 2 pts, PMIDs: 21820307, 21186264) and two phase unknown (c.191dup, 0.5 pts, ClinVar SCV001371267.12 internal data communication; c.989dup, 0.5 pts, PMID: 23606453). One individual was homozygous for the variant (0.5 pts, ClinVar SCV000767092.3 internal data communication) (PM3_Strong). At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness (PP4; PMD: 21820307). The variant has been reported to segregate with the LGMD phenotype in four affected family members from two families (PP1_Strong; PMID: 21186264, 23670307). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/15424 alleles) in the European (non-Finnish) population, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.88, which exceeds 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_Strong, PP1_Strong, PP4, PM2_Supporting, PP3.
Met criteria codes
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/15424 alleles) in European (non-Finnish) population, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting).
PM3_Strong
This variant has been detected in at least 6 individuals with autosomal recessive limb-girdle muscular dystrophy. Of those individuals, 5 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, with 3 of those confirmed in trans by parental testing (c.191dup x2, 2 pt, PMIDs: 21820307, 21186264) and 2 were phase unknown (c.191dup, 0.5 pt, ClinVar SCV001371267.12; c.989dup, 0.5 pts, PMID: 23606453). 1 individual was homozygous for the variant (0.5pt, ClinVar SCV000767092.3). A total of 3.5 pts meet criteria for PM3_Strong.
PP4
At least one patient with this variant displayed progressive weakness, which is specific for autosomal recessive limb-girdle muscular dystrophy (PP4_Supporting, PMD: 21820307).
PP3
The computational predictor REVEL gives a score of 0.884, which exceeds the threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3).
PP1_Strong
The variant has been reported to segregate with autosomal recessive limb-girdle muscular dystrophy in 2 affected family members from 2 families (PP1_Strong; PMID: 21186264, 23670307).
Not Met criteria codes
BS4
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
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
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
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
BP3
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
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
PS1
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
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
PM6
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
Curation History
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