ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.2521C>G (p.His841Asp) (rs781027702)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000176339 SCV000329068 pathogenic not provided 2015-07-07 criteria provided, single submitter clinical testing The H841D missense variant in the ANO5 gene has been reported previously in an individual with limb-girdle muscular dystrophy type 2L also known as, anoctaminopathy, who was heterozygous for this change and did not have another identifiable variant (Sarkozy et al., 2013). H841D was subsequently identified in an individual with limb-girdle muscular dystrophy type 2L who was compound heterozygous for H841D and another ANO5 variant(Leung et al., 2014). The H841D pathogenic variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in silico analysis predicts this sequence change is probably damaging to the protein structure/function, and other missense variants in nearby residues (M833K, M839R) have been reported in the Human Gene Mutation Database in association with ANO5-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Given the available evidence, we interpret H841D as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000176339 SCV000331780 likely pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778321 SCV000914507 uncertain significance ANO5-Related Disorders 2019-01-10 criteria provided, single submitter clinical testing The ANO5 c.2521C>G (p.His841Asp) missense variant has been reported in two studies in which it is found in a total of three patients, including one individual with suspected limb-girdle muscular dystrophy type 2L in a heterozygous state (Sarkozy et al. 2013) and two affected siblings in a compound heterozygous state (Leung et al. 2014). The p.His841Asp variant was observed in cis with a second variant that was predicted to be benign and in trans with a third known pathogenic variant in the two siblings. In addition, the p.His841Asp variant was present in cis with the second variant in a heterozygous state in one of the sibling's unaffected children (Leung et al. 2014). Control data are unavailable for this variant which is reported at a frequency of 0.00009 in the Latino population of the Genome Aggregation Database. Based on the evidence, the ANO5 p.His841Asp variant is classified as a variant of unknown significance but suspicious for pathogenicity for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000791570 SCV000930827 likely pathogenic Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2019-03-22 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 841 of the ANO5 protein (p.His841Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is present in population databases (rs781027702, ExAC 0.003%). This variant has been observed in trans with a pathogenic variant in an individual affected with ANO5-related disease and has been observed to segregate with disease in this individual's family (PMID: 24022920). It has also been observed in the heterozygous state in an individual with clinical features consistent ANO5-related disorders (PMID: 23606453). ClinVar contains an entry for this variant (Variation ID: 195705). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001254725 SCV001430803 uncertain significance Limb-girdle muscular dystrophy 2020-05-29 criteria provided, single submitter research The p.His841Asp variant in ANO5 was identified by our study in 1 individual with limb-girdle muscular dystrophy, along with a variant of uncertain significance. The variant in ANO5 has been reported in 4 individuals with limb-girdle muscular dystrophy, including the one from our study (PMID: 31395899, 24022920, 23606453). The presence of this variant in combination with a reported pathogenic variant, and in an individual with limb-girdle muscular dystrophy increases the likelihood that the p.His841Asp variant is pathogenic (Variation ID: 424764; PMID: 24022920). This variant has been identified in 0.009% (3/34378) of Latino chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP (rs781027702). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic by GeneDx, likley pathogenic by Invitae and EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, and as a variant of uncertain significance by Illumina Clinical Services Laboratory, Illumina (Variation ID:195705). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM3 (Richards 2015).

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