Submissions for variant NM_213599.3(ANO5):c.1640G>A (p.Arg547Gln)

gnomAD frequency: 0.00009  dbSNP: rs139618850

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000322343	SCV000333848	uncertain significance	not provided	2015-08-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778318	SCV000914504	uncertain significance	ANO5-related disorder	2017-04-28	criteria provided, single submitter	clinical testing	The ANO5 c.1640G>A (p.Arg547Gln) variant has been reported in three studies in which it is found in a total of four individuals with ANO5-Related Disorders, including in a compound heterozygous state with a known pathogenic variant in two brothers, and in a heterozygous state without a second identified variant in two additional unrelated individuals (van der Kooi et al. 2013; Sarkozy et al. 2013; Savarese et al. 2015). The two heterozygous individuals identified with this variant had a clinical suspicion of limb girdle muscualr dystrophy or nonspecific myopathic features, but no definitive clinical diagnoses (Sarkozy et al. 2013; Savarese et al. 2015). The p.Arg547Gln variant was absent from 52 controls (Savarese et al. 2015), but is reported at a frequency of 0.00227 in the African population of the 1000 Genomes Project. The evidence for this variant is limited. The p.Arg547Gln variant is therefore 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	RCV000807697	SCV000947763	pathogenic	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 547 of the ANO5 protein (p.Arg547Gln). This variant is present in population databases (rs139618850, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 23606453, 23607914, 25891276, 30564623, 31350120). 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: 282394). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANO5 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000322343	SCV003811564	likely pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323487	SCV004029989	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: ANO5 c.1640G>A (p.Arg547Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 250836 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in ANO5 causing Autosomal Recessive Limb-Girdle Muscular Dystrophy (0.00014 vs 0.0047), allowing no conclusion about variant significance. c.1640G>A has been reported at a compound heterozygous state along with a second apparently pathogenic variant in multiple individuals affected with Autosomal Recessive Limb-Girdle Muscular Dystrophy or Anoctaminopathy (examples: vanderKooi_2013, Cai_2019, TenDam_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of normal electrophysiological characters in a HEK293-based expression system consistent with an incompatible TMEM16E (ANO5) protein activity (DiZanni_2020). The following publications have been ascertained in the context of this evaluation (PMID: 31350120, 32112655, 30919934, 23607914). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic: n=1; Likely pathogenic: n=1; Affects: n=1; Uncertain significance: n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000322343	SCV005413971	likely pathogenic	not provided	2024-02-22	criteria provided, single submitter	clinical testing	PM2, PM3_supporting, PS3
Fulgent Genetics, Fulgent Genetics	RCV005044527	SCV005675910	pathogenic	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L; Miyoshi muscular dystrophy 3	2024-04-15	criteria provided, single submitter	clinical testing
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	RCV000758149	SCV000882765	affects	Autosomal recessive limb-girdle muscular dystrophy type 2L; Miyoshi muscular dystrophy 3	2019-02-11	no assertion criteria provided	research	The proband has another variant, NM_213599.2: c.1158delT.