ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.191dupA (rs137854521)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ANO5 @LOVD RCV000082844 SCV000172417 not provided not provided no assertion provided not provided
Athena Diagnostics Inc RCV000082844 SCV000255643 pathogenic not provided 2017-07-12 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000002248 SCV000693897 pathogenic Limb-girdle muscular dystrophy, type 2L 2017-06-26 criteria provided, single submitter research The c.191dupA pathogenic variant is previously described Founder mutation within the Northern European population (PMID: 21186264).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414931 SCV000492753 pathogenic Muscular Diseases 2015-10-02 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000627021 SCV000747724 pathogenic Elevated serum creatine phosphokinase; Polycystic kidney dysplasia; Achilles tendon contracture; Lower limb amyotrophy; Lower limb muscle weakness 2017-01-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082844 SCV000231252 pathogenic not provided 2016-08-08 criteria provided, single submitter clinical testing The c.191dupA ANO5 variant is a common pathogenic variant in the northern European population.1,2 1. Hicks et al. Brain. 2011 Jan;134(Pt 1):171-82. 2. Sarkozy et al. Hum Mutat. 2013 Aug;34(8):1111-8. AKT 4-29-16
GeneDx RCV000082844 SCV000329066 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing The c.191dupA pathogenic variant in the ANO5 gene was initially reported in the compound heterozygous state along with another ANO5 pathogenic variant in an individual with limb-girdle muscular dystrophy type 2L and in the homozygous state in three siblings with Miyoshi muscular dystrophy 3 (Bolduc et al., 2010). The c.191dupA pathogenic variant is considered to be a founder mutation within the Northern European population (Hicks et al., 2011). A few individuals who were compound heterozygous for the c.191dupA pathogenic variant and another pathogenic variant were reported to have left ventricular dilatation and dilated cardiomyopathy (Wahbi et al., 2013). The c.191dupA variant is observed in 257/125,188 (0.2%) alleles from individuals of non-Finnish European background, including two unrelated homozygous individuals, in large population cohorts (Lek et al., 2016). The c.191dupA pathogenic variant causes a frameshift starting with codon Asparagine 64, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Asn64LysfsX15. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret c.191dupA as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000778317 SCV000914503 pathogenic ANO5-Related Disorders 2018-08-29 criteria provided, single submitter clinical testing The ANO5 c.191dupA (p.Asn64LysfsTer15) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Asn64LysfsTer15 variant has been identified in at least 78 individuals with limb-girdle muscular dystrophy including 36 homozygotes and 42 compound heterozygotes; in two individuals with hyperCKemia in a compound heterozygous state; two individuals with myopathy, one in a homozygous state and one in a compound heterozygous state; three siblings with Miyoshi myopathy in a homozygous state; and eight individuals in a heterozygous state (Bolduc et al. 2010; Hicks et al. 2011; Deschauer et al. 2011; Penttiläet al. 2012; Magri et al. 2012; Sarkozy et al, 2013; Van der Kooi et al. 2013). The p.Asn64LysfsTer15 variant is reported as being one of the most common ANO5 pathogenic variants found in Northern European populations (Hicks et al., 2011). The p.Asn64LysfsTer15 variant has been reported in three of at least 500 control subjects and is reported at a frequency of 0.002186 in the population of the Exome Sequencing Project. Based on the potential impact of frameshift variants and collective evidence from the literature, the p.Asn64LysfsTer15 variant is classified as pathogenic for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000627781 SCV000645880 pathogenic Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2019-01-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn64Lysfs*15) in the ANO5 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs575136178, ExAC 0.2%). This variant is clearly defined as a limb girdle muscular dystrophy 2L (LGMD2L) causative allele (PMID: 21186264, 23606453). It is a founder mutation in the Northern European population, and is a common cause of limb girdle muscular dystrophy (PMID: 20096397, 21186264, 21739273, 23607914). ClinVar contains an entry for this variant (Variation ID: 2164). Loss-of-function variants in ANO5 are known to be pathogenic (PMID: 21186264, 23606453, 25891276). For these reasons, this variant has been classified as Pathogenic.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000002248 SCV000882597 likely pathogenic Limb-girdle muscular dystrophy, type 2L 2018-10-08 criteria provided, single submitter clinical testing
OMIM RCV000002247 SCV000022405 pathogenic Miyoshi muscular dystrophy 3 2012-03-20 no assertion criteria provided literature only
OMIM RCV000002248 SCV000809056 pathogenic Limb-girdle muscular dystrophy, type 2L 2012-03-20 no assertion criteria provided literature only

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