Submissions for variant NM_213599.3(ANO5):c.692G>T (p.Gly231Val)

gnomAD frequency: 0.00098  dbSNP: rs137854523

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082853	SCV000232828	pathogenic	not provided	2016-07-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000082853	SCV000329637	pathogenic	not provided	2022-10-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23193613, 22402862, 23670307, 26810512, 30564623, 30919934, 33879512, 23047743, 22742934, 23041008, 25891276, 22980763, 20096397, 28489263, 31353849, 31931849, 31980526, 32399982, 34426522, 31589614, 32367299, 32528171, 32925086, 34008892, 32403337)
Illumina Laboratory Services, Illumina	RCV000369126	SCV000369971	pathogenic	ANO5-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	The ANO5 c.692G>T (p.Gly231Val) missense variant has been reported in five studies in which it is found in a total of nine individuals with ANO5-Related Disorders, including in one individual in a homozygous state, in six individuals in a compound heterozygous state (including two siblings), in one individual in a heterozygous state in whom a second variant was not found, and in one individual in a heterozygous state as part of a complex allele with another missense variant (Bolduc et al. 2010; Wahbi et al. 2013; Penttilä et al. 2012; Sarkozy et al. 2012; Savarese et al. 2015). The p.Gly231Val variant was absent from 210 control chromosomes, but is reported at a frequency of 0.00402 in the Latino population of the Exome Aggregation Consortium. The Gly231 residue is conserved. Based on the collective evidence the p.Gly231Val 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	RCV000627782	SCV000645882	likely pathogenic	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 231 of the ANO5 protein (p.Gly231Val). This variant is present in population databases (rs137854523, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with limb-girdle muscular dystrophy type 2 (LGMD2), Miyoshi-like muscle dystrophy, and hyperCKemia (PMID: 20096397, 22402862, 22980763, 23041008, 23606453, 23670307, 25891276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2165). Advanced 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 at Invitae 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. 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.
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000002249	SCV000882598	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2018-10-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762830	SCV000893189	pathogenic	Gnathodiaphyseal dysplasia; Autosomal recessive limb-girdle muscular dystrophy type 2L; Miyoshi muscular dystrophy 3	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825558	SCV000966878	pathogenic	Hereditary fructosuria	2018-08-30	criteria provided, single submitter	clinical testing	The p.Gly231Val variant in ANO5 has been previously reported in at least 15 comp ound heterozygous and 1 homozygous individuals with ANO5-related muscle diseases , ranging from asymptomatic hyperCKemia to limb-girdle muscular dystrophy type 2L (LGMD2L) or Miyoshi muscular dystrophy, and segregated with disease in one co mpound heterozygous sibling. Three of these individuals were female and presente d with asymptomatic hyperCKemia (Bolduc 2010, Wahbi 2013, Savarese 2015, Penttil a 2012, Witting 2013, Liewluck 2013, Sarkozy 2013). Typically, females have mil der disease manifestations than males (Bolduc 2010, Penttila 2012). This variant has also been reported in ClinVar (Variation ID 2165) and identified in 0.113% (143/126350) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the g eneral population, its frequency is low enough to be consistent with the disease prevalence. Computational prediction tools and conservation analysis suggest th at the p.Gly231Val variant may impact the protein. In summary, this variant meet s criteria to be classified as pathogenic for ANO5-related muscle diseases in an autosomal recessive manner based upon proband count. ACMG/AMP Criteria applied: PP3, PP1, PM3_Very Strong.
Mendelics	RCV000002249	SCV001138251	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2022-12-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000082853	SCV001245647	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	ANO5: PM3:Very Strong, PM2, PP4, BP4
Revvity Omics, Revvity	RCV000082853	SCV002017247	pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing
3billion	RCV000002249	SCV002058403	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002165, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 25891276, 22402862, 23606453, 22980763, PM3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000970, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000002249	SCV002579896	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2022-07-15	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000002249	SCV002768606	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Both dominant and recessive condition have been reported in this gene with no clear genotype and phenotype correlation (PMID: 25891276, PMID: 28176803). (N) 0200 - Variant is predicted to result in a missense amino acid change from a glycine to a valine (exon 8 of 22). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (272 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant is highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (dimerisation domain of Ca+-activated chloride-channel, anoctamin; PDB, NBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple patients with ANO5-related myopathy, in a homozygous state or compound heterozygous with another variant (ClinVar, PMID: 31353849) (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
PreventionGenetics, part of Exact Sciences	RCV000369126	SCV004111816	pathogenic	ANO5-related disorder	2024-01-04	criteria provided, single submitter	clinical testing	The ANO5 c.692G>T variant is predicted to result in the amino acid substitution p.Gly231Val. This variant has been reported in several unrelated individuals to be causative for limb girdle muscular dystrophy 2L (Bolduc et al. 2010. PubMed ID: 20096397; Wahbi et al. 2013. PubMed ID: 23041008; Savarese et al. 2015. PubMed ID: 25891276). In addition, we have seen this variant in the homozygous and compound heterozygous state in other patients at PreventionGenetics with muscular dystrophy. This variant is reported in 0.27% of alleles in individuals of Latino descent in gnomAD. In summary, we categorize the c.692G>T variant as pathogenic for autosomal recessive ANO5-related disorders.
Athena Diagnostics	RCV000082853	SCV004229946	pathogenic	not provided	2023-03-21	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 has been identified in multiple unrelated individuals with clinical features associated with limb girdle muscular dystrophy. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
Molecular Genetics, Royal Melbourne Hospital	RCV003993729	SCV004812391	likely pathogenic	Miyoshi muscular dystrophy 3	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in ANO5 is predicted to replace glycine with valine at codon 231, p.(Gly231Val). The glycine residue is moderately conserved (100 vertebrates, UCSC), and is located in a cytoplasmic domain. There is a large physicochemical difference between glycine and valine. The highest population minor allele frequency in gnomAD v2.1 is 0.3% (95/35,372 alleles, 1 homozygote) in the Latino/admixed American population. This variant has been detected as homozygous or compound heterozygous with a second pathogenic allele in multiple individuals with limb-girdle muscular dystrophy, hyperCKaemia, and pseudo-metabolic myopathy phenotypes. The variants were confirmed in trans by parental testing in at least one of the compound heterozygous individuals (PMID: 20096397, 31353849). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_VeryStrong.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993730	SCV004813464	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2024-02-07	criteria provided, single submitter	clinical testing	Variant summary: ANO5 c.692G>T (p.Gly231Val) results in a non-conservative amino acid change located in the Anoctamin, dimerisation domain (IPR032394) of 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 0.001 in 250958 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.001 vs 0.0047), allowing no conclusion about variant significance. c.692G>T has been reported in the literature in multiple bi-allelic individuals affected with muscular dystrophy type 2 (LGMD2), Miyoshi-like muscle dystrophy, and hyperCKemia (examples: Bolduc_2010, Wahbi_2013, Savarese_2015, TenDam_2019, and Gonzalez-Quereda_2020). 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: 20096397, 23041008, 30919934, 32403337, 25891276). ClinVar contains an entry for this variant (Variation ID: 2165). Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000002249	SCV005042732	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L		criteria provided, single submitter	clinical testing
OMIM	RCV000002249	SCV000022407	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2L	2010-02-12	no assertion criteria provided	literature only
GeneReviews	RCV000002249	SCV000056226	not provided	Autosomal recessive limb-girdle muscular dystrophy type 2L		no assertion provided	literature only
ANO5 @LOVD	RCV000082853	SCV000172430	not provided	not provided		no assertion provided	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000082853	SCV001553936	pathogenic	not provided		no assertion criteria provided	clinical testing	The ANO5 p.G231V variant was identified as a compound heterozygous or homozygous variant in 17 of 1650 proband chromosomes (frequency: 0.01) from individuals with limb-girdle muscular dystrophy, hyperCKemia or mild dystrophic changes (Savarese_2015_PMID:25891276; Silva_2019_PMID:31353849; Bolduc_2010_PMID:20096397). The variant was identified in dbSNP (ID: rs137854523) and ClinVar (classified as pathogenic by GeneDx, Laboratory for Molecular Medicine and four other laboratories, and as likely pathogenic by Invitae and NeuroMeGen, Hospital Clinico Santiago de Compostela). The variant was identified in control databases in 274 of 282336 chromosomes (1 homozygous) at a frequency of 0.0009705 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 95 of 35372 chromosomes (freq: 0.002686), Other in 17 of 7204 chromosomes (freq: 0.00236), European (non-Finnish) in 152 of 128838 chromosomes (freq: 0.00118), Ashkenazi Jewish in 3 of 10360 chromosomes (freq: 0.00029), African in 5 of 24968 chromosomes (freq: 0.0002) and European (Finnish) in 2 of 25092 chromosomes (freq: 0.00008), but was not observed in the East Asian or South Asian populations. The p.Gly231 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000082853	SCV001743656	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000082853	SCV001798134	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000082853	SCV001808041	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000082853	SCV001972085	likely pathogenic	not provided		no assertion criteria provided	clinical testing