ClinVar Miner

Submissions for variant NM_213599.3(ANO5):c.1627dup (p.Met543fs)

dbSNP: rs281865480
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000790803 SCV000339172 pathogenic not provided 2016-01-25 criteria provided, single submitter clinical testing The c.1627dupA ANO5 pathogenic variant has been reported in individuals with LGMD2L1 and is of a type expected to cause disease. 1. www.lovd.nl/ANO5 AKT 9-7-16
Invitae RCV000791428 SCV000645876 pathogenic Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L 2023-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met543Asnfs*11) in the ANO5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO5 are known to be pathogenic (PMID: 21186264, 23606453, 25891276, 30919934). This variant is present in population databases (rs768746440, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with ANO5-related myopathies and/or limb girdle muscular dystrophy 2L (PMID: 22194990, 22402862, 22742934, 23606453, 25891276). ClinVar contains an entry for this variant (Variation ID: 285942). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000327025 SCV000786703 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2L criteria provided, single submitter research The homozgous c.1627dupA variant was identified by our study in one individual with Limb-Girdle Muscular Dystrophy. The c.1627dupA variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV001729507 SCV001976865 pathogenic Miyoshi muscular dystrophy 3 2021-10-01 criteria provided, single submitter clinical testing PVS1, PM2, PP3
MGZ Medical Genetics Center RCV000327025 SCV002580987 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2L 2022-07-15 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001729507 SCV003761307 pathogenic Miyoshi muscular dystrophy 3 2023-01-25 criteria provided, single submitter curation The homozygous p.Met543AsnfsTer11 variant in ANO5 was identified by our study in one individual with limb-girdle muscular dystrophy. The p.Met543AsnfsTer11 variant in ANO5 has been previously reported in 8 unrelated individuals with ANO5-related muscle disease (PMID: 34008892, PMID: 30919934, PMID: 25891276, PMID: 23606453, PMID: 22742934, PMID: 22402862, PMID: 22194990) and segregated with disease in 4 affected relatives from 2 families, but has been identified in 0.01% (4/35334) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1412514693). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 8 affected individuals, 3 were homozygotes (PMID: 30919934, PMID: 25891276, PMID: 22742934) and 4 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 22194990, PMID: 23606453, ClinVar Variation ID: 2164; PMID: 34008892, ClinVar Variation ID: 2166), which increases the likelihood that the p.Met543AsnfsTer11 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 285942) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 543 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ANO5 gene is an established disease mechanism in autosomal recessive ANO5-related muscle disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ANO5-related muscle disease. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong, PP1 (Richards 2015).

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