NM_144672.4(OTOA):c.1879C>T (p.Pro627Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 18, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV002281927.3

Allele description [Variation Report for NM_144672.4(OTOA):c.1879C>T (p.Pro627Ser)]

NM_144672.4(OTOA):c.1879C>T (p.Pro627Ser)

Gene:

OTOA:otoancorin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_144672.4(OTOA):c.1879C>T (p.Pro627Ser)

HGVS:

NC_000016.10:g.21722977C>T
NG_012973.2:g.63845C>T
NM_001161683.2:c.1642C>T
NM_144672.4:c.1879C>TMANE SELECT
NM_170664.3:c.907C>T
NP_001155155.1:p.Pro548Ser
NP_653273.3:p.Pro627Ser
NP_733764.1:p.Pro303Ser
NC_000016.9:g.21734298C>T
NG_012973.1:g.49464C>T
NM_144672.3:c.1879C>T

Protein change:

P303S; PRO627SER

Links:

OMIM: 607038.0004; dbSNP: rs587777133

NCBI 1000 Genomes Browser:

rs587777133

Molecular consequence:

NM_001161683.2:c.1642C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_144672.4:c.1879C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170664.3:c.907C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002571314	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 10, 2022)	germline	clinical testing	Citation Link,
SCV004297686	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23173898, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002571314

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Mar 10, 2022)

germline

clinical testing

Citation Link,

SCV004297686

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 18, 2024)

germline

clinical testing

PubMed (2)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel OTOA mutations cause autosomal recessive non-syndromic hearing impairment in Pakistani families.

Lee K, Chiu I, Santos-Cortez RL, Basit S, Khan S, Azeem Z, Andrade PB, Kim SS, Ahmad W, Leal SM.

Clin Genet. 2013 Sep;84(3):294-6. doi: 10.1111/cge.12047. Epub 2012 Nov 23. No abstract available.

PubMed [citation]

PMID:: 23173898
PMCID:: PMC6220893

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV002571314.2

#	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: 23173898, 24963352, 31527525)

#	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 Invitae, SCV004297686.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 627 of the OTOA protein (p.Pro627Ser). This variant is present in population databases (rs587777133, gnomAD 0.03%). This missense change has been observed in individuals with deafness (PMID: 23173898). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 100655). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.

#	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: Feb 20, 2024

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