NM_213599.3(ANO5):c.1538C>T (p.Thr513Ile) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 10, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000553314.10

Allele description [Variation Report for NM_213599.3(ANO5):c.1538C>T (p.Thr513Ile)]

NM_213599.3(ANO5):c.1538C>T (p.Thr513Ile)

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.1538C>T (p.Thr513Ile)

HGVS:

NC_000011.10:g.22259649C>T
NG_015844.1:g.71474C>T
NM_001142649.2:c.1535C>T
NM_213599.3:c.1538C>TMANE SELECT
NP_001136121.1:p.Thr512Ile
NP_998764.1:p.Thr513Ile
NP_998764.1:p.Thr513Ile
LRG_868t1:c.1538C>T
LRG_868:g.71474C>T
LRG_868p1:p.Thr513Ile
NC_000011.9:g.22281195C>T
NM_213599.2:c.1538C>T
Q75V66:p.Thr513Ile

Protein change:

T512I

Links:

UniProtKB: Q75V66#VAR_076477; dbSNP: rs281865467

NCBI 1000 Genomes Browser:

rs281865467

Molecular consequence:

NM_001142649.2:c.1535C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_213599.3:c.1538C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Gnathodiaphyseal dysplasia (GDD)
Synonyms:: GNATHODIAPHYSEAL SCLEROSIS; Osteogenesis imperfecta Levin type; Levin syndrome 2; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008151; MedGen: C1833736; OMIM: 166260

Name:: Autosomal recessive limb-girdle muscular dystrophy type 2L (LGMDR12)
Synonyms:: Limb-girdle muscular dystrophy, type 2L; MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 12
Identifiers:: MONDO: MONDO:0012652; MedGen: C1969785; Orphanet: 206549; OMIM: 611307

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000645892	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29124309, 23047743, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000645892

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 10, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Gain of function of TMEM16E/ANO5 scrambling activity caused by a mutation associated with gnathodiaphyseal dysplasia.

Di Zanni E, Gradogna A, Scholz-Starke J, Boccaccio A.

Cell Mol Life Sci. 2018 May;75(9):1657-1670. doi: 10.1007/s00018-017-2704-9. Epub 2017 Nov 9.

PubMed [citation]

PMID:: 29124309
PMCID:: PMC5897490

A novel missense mutation in ANO5/TMEM16E is causative for gnathodiaphyseal dyplasia in a large Italian pedigree.

Marconi C, Brunamonti Binello P, Badiali G, Caci E, Cusano R, Garibaldi J, Pippucci T, Merlini A, Marchetti C, Rhoden KJ, Galietta LJ, Lalatta F, Balbi P, Seri M.

Eur J Hum Genet. 2013 Jun;21(6):613-9. doi: 10.1038/ejhg.2012.224. Epub 2012 Oct 10.

PubMed [citation]

PMID:: 23047743
PMCID:: PMC3658193

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000645892.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ANO5 function (PMID: 29124309). 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. ClinVar contains an entry for this variant (Variation ID: 288853). This missense change has been observed in individual(s) with autosomal dominant gnathodiaphyseal dysplasia (PMID: 23047743). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 513 of the ANO5 protein (p.Thr513Ile).

#	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

Last Updated: Sep 29, 2024

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