NM_133261.3(GIPC3):c.122C>A (p.Thr41Lys) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 21, 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:: RCV000413083.7

Allele description [Variation Report for NM_133261.3(GIPC3):c.122C>A (p.Thr41Lys)]

NM_133261.3(GIPC3):c.122C>A (p.Thr41Lys)

Gene:

GIPC3:GIPC PDZ domain containing family member 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.3

Genomic location:

Preferred name:

NM_133261.3(GIPC3):c.122C>A (p.Thr41Lys)

HGVS:

NC_000019.10:g.3585719C>A
NG_031943.1:g.5149C>A
NM_133261.3:c.122C>AMANE SELECT
NP_573568.1:p.Thr41Lys
NC_000019.9:g.3585717C>A
NM_133261.2:c.122C>A

Protein change:

T41K

Links:

dbSNP: rs727503062

NCBI 1000 Genomes Browser:

rs727503062

Molecular consequence:

NM_133261.3:c.122C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000491294	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Mar 8, 2023)	germline	clinical testing	Citation Link,
SCV004297979	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23510777, 32747562, 32864763, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000491294

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Mar 8, 2023)

germline

clinical testing

Citation Link,

SCV004297979

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 21, 2023)

germline

clinical testing

PubMed (4)
[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

Homozygosity mapping identifies a novel GIPC3 mutation causing congenital nonsyndromic hearing loss in a Saudi family.

Ramzan K, Al-Owain M, Allam R, Berhan A, Abuharb G, Taibah K, Imtiaz F.

Gene. 2013 May 25;521(1):195-9. doi: 10.1016/j.gene.2013.03.042. Epub 2013 Mar 16.

PubMed [citation]

PMID:: 23510777

Genomic analysis of inherited hearing loss in the Palestinian population.

Abu Rayyan A, Kamal L, Casadei S, Brownstein Z, Zahdeh F, Shahin H, Canavati C, Dweik D, Jaraysa T, Rabie G, Carlson RJ, Gulsuner S, Lee MK, Avraham KB, Walsh T, King MC, Kanaan MN.

Proc Natl Acad Sci U S A. 2020 Aug 18;117(33):20070-20076. doi: 10.1073/pnas.2009628117. Epub 2020 Aug 3.

PubMed [citation]

PMID:: 32747562
PMCID:: PMC7443947

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000491294.4

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); 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: 31589614, 32864763, 23510777, 32747562)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004297979.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 41 of the GIPC3 protein (p.Thr41Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with nonsyndromic deafness (PMID: 23510777, 32747562, 32864763). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 163502). 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 not expected to disrupt GIPC3 protein function. 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: Apr 7, 2025

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