Submissions for variant NM_213599.3(ANO5):c.2521C>G (p.His841Asp)

gnomAD frequency: 0.00004  dbSNP: rs781027702

Total submissions: 8

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.
Eurofins Ntd Llc (ga)	RCV000176339	SCV000331780	likely pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778321	SCV000914507	uncertain significance	ANO5-related disorder	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791570	SCV000930827	pathogenic	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 841 of the ANO5 protein (p.His841Asp). This variant is present in population databases (rs781027702, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 24022920, 31395899, 32403337). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 195705). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ANO5 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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, http://gnomad.broadinstitute.org; 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).
Revvity Omics, Revvity	RCV000176339	SCV002021396	likely pathogenic	not provided	2021-09-07	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000176339	SCV002771484	likely pathogenic	not provided	2021-07-20	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in at least one family. Computational tools predict that this variant is damaging.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330536	SCV004037657	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: ANO5 c.2521C>G (p.His841Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 249618 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (4.8e-05 vs 0.0047), allowing no conclusion about variant significance. c.2521C>G has been reported in the literature in multiple compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g., Leung_2014, Jarmula_2019, Gonzalez-Quereda_2020, Segui_2020, Topf_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32403337, 31395899, 24022920, 23606453, 32528171, 32399949). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (pathogenic, n = 2; likely pathogenic, n = 3, uncertain significance, n = 2). Based on the evidence outlined above, the variant was classified as likely pathogenic.