11-22274605-C-T

Position:

chr11-22274605-C-T

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3PP4PM3PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_213599.3: c.2272C>T variant in ANO5 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 758 (p.Arg758Cys). This variant has been detected in at least 7 individuals with LGMD, five of whom had a second ANO5 variant classified as pathogenic or likely pathogenic, with one confirmed in trans by parental testing (c.191dup x5, 3.0 pts, PMID:25135358, 24803842, 21739273, 21186264). Two patients were homozygous for the variant (1.0 pt, PMID:20096397) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4; PMD: 31395899). The variant has been reported to segregate with LGMD in six affected family members from three families (PP1_Strong; PMID:20096397, 27911336). The maximum minor allele frequency for this variant is 0.0003116 (40/128354 chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which exceeds the VCEP threshold of 0.0001 for PM2 (criterion not met). The computational predictor REVEL gives a score of 0.82, which meets the VCEP threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3_Very Strong, PP4, PP1_Strong, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA130516/MONDO:0015152/188

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 1 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:20O:2

Conservation

PhyloP100: 6.04

Variant links:

Genes affected

ANO5 (HGNC:27337): (anoctamin 5) This gene encodes a member of the anoctamin family of transmembrane proteins. The encoded protein is likely a calcium activated chloride channel. Mutations in this gene have been associated with gnathodiaphyseal dysplasia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

ANO5 links:

ANO5 (HGNC:):

ANO5 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 8 ACMG points.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO5	NM_213599.3 linkuse as main transcript	c.2272C>T	p.Arg758Cys	missense_variant	20/22	ENST00000324559.9	NP_998764.1	Q75V66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9 linkuse as main transcript	c.2272C>T	p.Arg758Cys	missense_variant	20/22	1	NM_213599.3	ENSP00000315371.9		Q75V66

Frequencies

GnomAD3 genomes

AF:

0.000455

AC:

AN:

151668

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00429

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000280

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000580

AC:

145

AN:

250082

Hom.:

AF XY:

0.000503

AC XY:

AN XY:

135158

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00534

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000305

AC:

444

AN:

1455736

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

225

AN XY:

722916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00556

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.000399

GnomAD4 genome

AF:

0.000455

AC:

AN:

151780

Hom.:

Cov.:

AF XY:

0.000634

AC XY:

AN XY:

74150

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00429

Gnomad4 NFE

AF:

0.000280

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.000185

Hom.:

ExAC

AF:

0.000453

AC:

EpiCase

AF:

0.000219

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:9Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 13, 2023	This variant is a common pathogenic variant associated with autosomal recessive muscular dystrophy and is considered a founder variant among individuals of Finnish ancestry (PMID: 27911336, 22402862). Therefore, the frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, including cases of limb girdle muscular dystrophy and Miyoshi myopathy, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2024	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: 26886200, 21739273, 37273706, 27911336, 24803842, 17132147, 31395899, 22980763, 21186264, 20096397, 30564623, 30919934, 25135358, 31341644, 28489263, 25891276, 22402862, 31589614, 34008892, 34418069, 35239206) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 12, 2022	PP1, PP3, PM3_strong, PS4 -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ANO5: PM3:Very Strong, PM2:Supporting, PP1, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	literature only	ANO5 @LOVD	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 28, 2023	- -

Autosomal recessive limb-girdle muscular dystrophy type 2L

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace arginine with cysteine at codon 758 of the ANO5 protein (p.(Arg758Cys)). The arginine residue is invariant across species (100 vertebrates, UCSC), and is located in the anoctamin domain. There is a large physicochemical difference between arginine and cysteine. The variant is present in a large population cohort at a frequency of 0.5% in the Finnish European population (rs137854529), and is recognised to be a Finnish founder mutation (PMID: 20096397, 22402862, 27911336; gnomAD v2.1.1 and v3.0). The frequency of the variant in the next most common population, European (non-Finnish), is 0.03%. This variant has been previously reported in affected individuals in homozygous state, and in heterozygous state along with another pathogenic variant (PM3_VeryStrong; PMID: 22402862, 21739273, 21186264, 22980763). It has been shown to segregate with disease in two affected siblings in the homozygous state (PP1; PMID: 20096397). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 5/6 algorithms). Based on the variant classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. The following criteria are met: PM3_VeryStrong, PP1, PP3. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Arg758Cys variant in ANO5 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.06604% (182/275600) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137854529). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg758Cys variant in ANO5 has been reported in 26 individuals with ANO5-associated muscular dystrophy in the literature and segregated with disease in 4 affected relatives from 2 families (PMID: 27911336, 22402862, 21739273, 21186264, 20096397, 22980763). The presence of this variant in combination with 5 reported pathogenic (or likely pathogenic) variants and in 15 individuals with muscular dystrophy increases the likelihood that the p.Arg758Cys variant is pathogenic (PMID: 22980763). This variant has also been reported pathogenic in ClinVar (Variation ID: 2166). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on reports in ClinVar and multiple occurrences with reported pathogenic ANO5 variants in individuals with muscular dystrophy. ACMG/AMP Criteria applied: PM2, PP3, PP1_Moderate, PM3_VeryStrong (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 20, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 28, 2014	The Arg758Cys variant in ANO5 has been reported in >20 homozygous and compound heterozygous individuals with muscular dystrophy and was found to segregate with disease in 3 affected relatives (Bolduc 2010, Hicks 2011, Penttila 2010, Sarkozy 2012). This variant has been identified in 1% (2/186) of Finnish chromosomes by the 1000 Genomes Project (dbSNP rs157854529) and is a known Finnish founder variant. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational analyses (biochemical amino acid properties, conservation, PolyPhen2, and SIFT) suggest that the p.Arg758Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

Miyoshi muscular dystrophy 3

Pathogenic:4Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM2, PM3, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 22, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 20, 2012	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_213599.2:c.2272C>T in the ANO5 gene has an allele frequency of 0.005 in European (Finnish) subpopulation in the gnomAD database. Sarkozy et al. reported two patients with Limb girdle muscular dystrophy type 2L harboring 2272C>T/191dupA (PMID: 22980763; PMID: 25135358). Bolduc et al reported a non-consanguineous Finnish patient suffering non-dysferlin Miyoshi myopathyharboing. The parents are carrier and two of their children are homozygous (PMID: 20096397). In addition, Penttila et al reported homozygous in 9 Finnish patients (PMID: 22402862). This variant is considered as a founder mutation in the Finnish population. Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PM3_Strong; PP3, PP1. -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Jan 07, 2025

The NM_213599.3: c.2272C>T variant in ANO5 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 758 (p.Arg758Cys). This variant has been detected in at least 7 individuals with LGMD, five of whom had a second ANO5 variant classified as pathogenic or likely pathogenic, with one confirmed in trans by parental testing (c.191dup x5, 3.0 pts, PMID: 25135358, 24803842, 21739273, 21186264). Two patients were homozygous for the variant (1.0 pt, PMID: 20096397) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4; PMD: 31395899). The variant has been reported to segregate with LGMD in six affected family members from three families (PP1_Strong; PMID: 20096397, 27911336). The maximum minor allele frequency for this variant is 0.0003116 (40/128354 chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which exceeds the VCEP threshold of 0.0001 for PM2 (criterion not met). The computational predictor REVEL gives a score of 0.82, which meets the VCEP threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3_Very Strong, PP4, PP1_Strong, PP3. -

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 758 of the ANO5 protein (p.Arg758Cys). This variant is present in population databases (rs137854529, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy, distal myopathy and Miyoshi myopathy (PMID: 20096397, 21186264, 21739273, 22402862, 22980763, 24803842, 25135358, 27911336). 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: 2166). 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) performed at Invitae 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.21

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

4.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MVP

0.89

MPC

0.54

ClinPred

0.33

GERP RS

5.2

Varity_R

0.81

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over