Submissions for variant NM_213599.3(ANO5):c.242A>G (p.Asp81Gly)

gnomAD frequency: 0.00010  dbSNP: rs199501657

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082846	SCV000331513	likely pathogenic	not provided	2017-04-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000082846	SCV000582412	likely pathogenic	not provided	2015-09-22	criteria provided, single submitter	clinical testing	The D81G variant has been reported previously the in compound heterozygous state in an individual with elevated CK levels and lower leg weakness (Penttilä et al., 2012). The D81G variant has also been reported in the compound heterozygous state in 3 family members, under the age of 35, with elevated CpK levels, mild weakness, and a family history of disease (Sarkozy et al., 2012). This substitution was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D81G 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, pathogenic missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with muscular dystrophy (Stenson et al., 2014). Therefore, this variant is a strong candidate for a pathogenic variant; however, the possibility that it is a benign variant cannot be excluded
CeGaT Center for Human Genetics Tuebingen	RCV000082846	SCV001502037	pathogenic	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377409	SCV001574736	pathogenic	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 81 of the ANO5 protein (p.Asp81Gly). This variant is present in population databases (rs199501657, gnomAD 0.08%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 22402862, 22980763, 31395899). ClinVar contains an entry for this variant (Variation ID: 96679). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700398	SCV005202713	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2024-07-10	criteria provided, single submitter	clinical testing	Variant summary: ANO5 c.242A>G (p.Asp81Gly) results in a non-conservative amino acid change located in the Anoctamin, dimerisation domain (IPR032394) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 250244 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00016 vs 0.0047), allowing no conclusion about variant significance. c.242A>G has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Penttila_2012, Sarkozy_2012, Jarmula_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22402862, 22980763, 31395899). ClinVar contains an entry for this variant (Variation ID: 96679). Based on the evidence outlined above, the variant was classified as pathogenic.