NM_001384140.1(PCDH15):c.131T>C (p.Val44Ala) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 17, 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:: RCV000522599.5

Allele description [Variation Report for NM_001384140.1(PCDH15):c.131T>C (p.Val44Ala)]

NM_001384140.1(PCDH15):c.131T>C (p.Val44Ala)

Genes:

PCDH15:protocadherin related 15 [Gene - OMIM - HGNC]
LOC105378311:uncharacterized LOC105378311 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

10q21.1

Genomic location:

Preferred name:

NM_001384140.1(PCDH15):c.131T>C (p.Val44Ala)

Other names:

NM_001384140.1(PCDH15):c.131T>C; p.Val44Ala

HGVS:

NC_000010.11:g.54527838A>G
NG_009191.3:g.1106345T>C
NM_001142763.2:c.146T>C
NM_001142764.2:c.131T>C
NM_001142765.2:c.131T>C
NM_001142766.2:c.131T>C
NM_001142767.2:c.131T>C
NM_001142768.2:c.91+136334T>C
NM_001142769.3:c.146T>C
NM_001142770.3:c.131T>C
NM_001142771.2:c.146T>C
NM_001142772.2:c.131T>C
NM_001142773.2:c.91+136334T>C
NM_001354404.2:c.91+136334T>C
NM_001354411.2:c.131T>C
NM_001354420.2:c.131T>C
NM_001354429.2:c.131T>C
NM_001354430.2:c.131T>C
NM_001384140.1:c.131T>CMANE SELECT
NM_033056.4:c.131T>C
NP_001136235.1:p.Val49Ala
NP_001136236.1:p.Val44Ala
NP_001136237.1:p.Val44Ala
NP_001136238.1:p.Val44Ala
NP_001136239.1:p.Val44Ala
NP_001136241.1:p.Val49Ala
NP_001136242.1:p.Val44Ala
NP_001136243.1:p.Val49Ala
NP_001136244.1:p.Val44Ala
NP_001341340.1:p.Val44Ala
NP_001341349.1:p.Val44Ala
NP_001341358.1:p.Val44Ala
NP_001341359.1:p.Val44Ala
NP_001371069.1:p.Val44Ala
NP_149045.3:p.Val44Ala
NC_000010.10:g.56287598A>G
NM_001142769.1:c.146T>C
NM_033056.3:c.131T>C

Protein change:

V44A

Links:

dbSNP: rs750302536

NCBI 1000 Genomes Browser:

rs750302536

Molecular consequence:

NM_001142768.2:c.91+136334T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001142773.2:c.91+136334T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354404.2:c.91+136334T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001142763.2:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142764.2:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142765.2:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142766.2:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142767.2:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142769.3:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142770.3:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142771.2:c.146T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001142772.2:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354411.2:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354420.2:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354429.2:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354430.2:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001384140.1:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033056.4:c.131T>C - 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
SCV000619232	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 7, 2020)	germline	clinical testing	Citation Link,
SCV001487685	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 17, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33111345, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000619232

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 7, 2020)

germline

clinical testing

Citation Link,

SCV001487685

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 17, 2022)

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

Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1.

Brownstein Z, Gulsuner S, Walsh T, Martins FTA, Taiber S, Isakov O, Lee MK, Bordeynik-Cohen M, Birkan M, Chang W, Casadei S, Danial-Farran N, Abu-Rayyan A, Carlson R, Kamal L, Arnthórsson AÖ, Sokolov M, Gilony D, Lipschitz N, Frydman M, Davidov B, Macarov M, et al.

Clin Genet. 2020 Oct;98(4):353-364. doi: 10.1111/cge.13817. Epub 2020 Aug 24.

PubMed [citation]

PMID:: 33111345
PMCID:: PMC8045518

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, SCV000619232.3

#	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 a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33111345)

#	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, SCV001487685.2

#	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 valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 44 of the PCDH15 protein (p.Val44Ala). This variant is present in population databases (rs750302536, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 33111345). This variant is also known as NM_001142769.1:c.146T>C Val49Ala. ClinVar contains an entry for this variant (Variation ID: 450626). 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 PCDH15 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Mar 30, 2024

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