NM_001145308.5(LRTOMT):c.242G>A (p.Arg81Gln) AND Autosomal recessive nonsyndromic hearing loss 63

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 29, 2022
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:: RCV000000573.5

Allele description [Variation Report for NM_001145308.5(LRTOMT):c.242G>A (p.Arg81Gln)]

NM_001145308.5(LRTOMT):c.242G>A (p.Arg81Gln)

Genes:

LRTOMT:leucine rich transmembrane and O-methyltransferase domain containing [Gene - OMIM - HGNC]
TOMT:transmembrane O-methyltransferase [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.4

Genomic location:

Preferred name:

NM_001145308.5(LRTOMT):c.242G>A (p.Arg81Gln)

HGVS:

NC_000011.10:g.72106094G>A
NG_021423.1:g.30759G>A
NM_001145308.5:c.242G>A
NM_001145309.4:c.242G>A
NM_001145310.4:c.122G>A
NM_001393500.2:c.143G>AMANE SELECT
NP_001138780.1:p.Arg81Gln
NP_001138780.1:p.Arg81Gln
NP_001138781.1:p.Arg81Gln
NP_001138782.1:p.Arg41Gln
NP_001380429.1:p.Arg48Gln
NC_000011.9:g.71817140G>A
NM_001145308.1:c.242G>A
NM_001145308.4:c.242G>A
Q8WZ04:p.Arg81Gln

Protein change:

R41Q; ARG81GLN

Links:

UniProtKB: Q8WZ04#VAR_054955; OMIM: 612414.0002; dbSNP: rs137853185

NCBI 1000 Genomes Browser:

rs137853185

Molecular consequence:

NM_001145308.5:c.242G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001145309.4:c.242G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001145310.4:c.122G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001393500.2:c.143G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 63
Synonyms:: Deafness, autosomal recessive 63
Identifiers:: MONDO: MONDO:0012670; MedGen: C1969621; Orphanet: 90636; OMIM: 611451

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020722	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2008)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002059017	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:22903915,
SCV002581628	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 29, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000020722

OMIM

no assertion criteria provided

Pathogenic
(Nov 1, 2008)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002059017

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 3, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

PMID:22903915,

SCV002581628

MGZ Medical Genetics Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 29, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans.

Ahmed ZM, Masmoudi S, Kalay E, Belyantseva IA, Mosrati MA, Collin RW, Riazuddin S, Hmani-Aifa M, Venselaar H, Kawar MN, Tlili A, van der Zwaag B, Khan SY, Ayadi L, Riazuddin SA, Morell RJ, Griffith AJ, Charfedine I, Caylan R, Oostrik J, Karaguzel A, Ghorbel A, et al.

Nat Genet. 2008 Nov;40(11):1335-40. doi: 10.1038/ng.245. Epub 2008 Oct 26.

PubMed [citation]

PMID:: 18953341
PMCID:: PMC3404732

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

Details of each submission

From OMIM, SCV000020722.1

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

Description

In affected individuals of a Tunisian family with DFNB63 (611451), Ahmed et al. (2008) identified a homozygous 242G-A transition in exon 8 of the LRTOMT gene, resulting in an arg81-to-gln (R81Q) substitution predicted to alter the COMT domain of LRTOMT2.

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

From 3billion, SCV002059017.1

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

Description

The variant was co-segregated with Deafness, autosomal recessive 63 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 18953341, PP1_S). It has been reported to be in trans as homozygous in at least one similarly affected unrelated individual (PMID: 18953341,PM3_P). A different missense change at the same codon has been reported to be associated with LRTOMT related disorder (PMID:22903915, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.701, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000026, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From MGZ Medical Genetics Center, SCV002581628.1

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

Last Updated: Oct 8, 2024

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