NM_213599.3(ANO5):c.692G>T (p.Gly231Val) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Dec 22, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000082853.47

Allele description

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

Gene:

ANO5:anoctamin 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p14.3

Genomic location:

Preferred name:

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

Other names:

G231V

HGVS:

NC_000011.10:g.22236206G>T
NG_015844.1:g.48031G>T
NM_001142649.2:c.689G>T
NM_213599.3:c.692G>TMANE SELECT
NP_001136121.1:p.Gly230Val
NP_998764.1:p.Gly231Val
NP_998764.1:p.Gly231Val
LRG_868t1:c.692G>T
LRG_868:g.48031G>T
LRG_868p1:p.Gly231Val
NC_000011.9:g.22257752G>T
NM_213599.2:c.692G>T
Q75V66:p.Gly231Val
p.(Gly231Val)

Protein change:

G230V; GLY231VAL

Links:

UniProtKB: Q75V66#VAR_063582; OMIM: 608662.0005; dbSNP: rs137854523

NCBI 1000 Genomes Browser:

rs137854523

Molecular consequence:

NM_001142649.2:c.689G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_213599.3:c.692G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Homologene neighbors for GEO Profiles (Select 95243018) (0)
GEO Profiles
LOC127885634 [Homo sapiens]
LOC127885634 [Homo sapiens]
Gene ID:127885634

Gene
Related DataSets for GEO Profiles (Select 40375364) (1)
GEO DataSets
Sevoflurane and propofol effect on the heart during off-pump coronary artery byp...
Sevoflurane and propofol effect on the heart during off-pump coronary artery bypass graft surgery
Accession: GDS2772

GEO DataSets
367830[uid] (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172430	ANO5 @LOVD	no classification provided	not provided	unknown	not provided	PubMed (1) [See all records that cite this PMID]
SCV000232828	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Jul 29, 2016)	germline	clinical testing	Citation Link,
SCV000329637	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 25, 2022)	germline	clinical testing	Citation Link,
SCV001245647	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2023)	germline	clinical testing	Citation Link,
SCV001553936	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV001743656	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001798134	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001808041	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001972085	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV002017247	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004229946	Athena Diagnostics Inc	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Mar 21, 2023)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 25891276, 23670307, 26810512, 23663589, 30919934, 32367299, 32528171, 31353849, 32403337, 31931849, 20096397, 23041008, 22980763, 22402862, 23606453, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	yes	9	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	28	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Next generation sequencing on patients with LGMD and nonspecific myopathies: Findings associated with ANO5 mutations.

Savarese M, Di Fruscio G, Tasca G, Ruggiero L, Janssens S, De Bleecker J, Delpech M, Musumeci O, Toscano A, Angelini C, Sacconi S, Santoro L, Ricci E, Claes K, Politano L, Nigro V.

Neuromuscul Disord. 2015 Jul;25(7):533-41. doi: 10.1016/j.nmd.2015.03.011. Epub 2015 Mar 30.

PubMed [citation]

PMID:: 25891276
PMCID:: PMC4502439

See all PubMed Citations (17)

Details of each submission

From ANO5 @LOVD, SCV000172430.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000232828.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	28	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		28	not provided	not provided	not provided

From GeneDx, SCV000329637.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001245647.20

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	not provided

Description

ANO5: PM3:Very Strong, PM2, PP4, BP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		9	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553936.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001743656.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV001798134.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001808041.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001972085.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002017247.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics Inc, SCV004229946.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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