NM_001384140.1(PCDH15):c.3101G>T (p.Arg1034Leu) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 20, 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:: RCV001806574.4

Allele description [Variation Report for NM_001384140.1(PCDH15):c.3101G>T (p.Arg1034Leu)]

NM_001384140.1(PCDH15):c.3101G>T (p.Arg1034Leu)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

10q21.1

Genomic location:

Preferred name:

NM_001384140.1(PCDH15):c.3101G>T (p.Arg1034Leu)

HGVS:

NC_000010.11:g.53959753C>A
NG_009191.3:g.1674430G>T
NM_001142763.2:c.3116G>T
NM_001142764.2:c.3101G>T
NM_001142765.2:c.2888G>T
NM_001142766.2:c.3101G>T
NM_001142767.2:c.2990G>T
NM_001142768.2:c.3035G>T
NM_001142769.3:c.3137G>T
NM_001142770.3:c.3101G>T
NM_001142771.2:c.3116G>T
NM_001142772.2:c.3101G>T
NM_001142773.2:c.3035G>T
NM_001354404.2:c.3035G>T
NM_001354411.2:c.3122G>T
NM_001354420.2:c.3101G>T
NM_001354429.2:c.3101G>T
NM_001384140.1:c.3101G>TMANE SELECT
NM_033056.4:c.3101G>T
NP_001136235.1:p.Arg1039Leu
NP_001136236.1:p.Arg1034Leu
NP_001136237.1:p.Arg963Leu
NP_001136238.1:p.Arg1034Leu
NP_001136239.1:p.Arg997Leu
NP_001136240.1:p.Arg1012Leu
NP_001136241.1:p.Arg1046Leu
NP_001136242.1:p.Arg1034Leu
NP_001136243.1:p.Arg1039Leu
NP_001136244.1:p.Arg1034Leu
NP_001136245.1:p.Arg1012Leu
NP_001341333.1:p.Arg1012Leu
NP_001341340.1:p.Arg1041Leu
NP_001341349.1:p.Arg1034Leu
NP_001341358.1:p.Arg1034Leu
NP_001371069.1:p.Arg1034Leu
NP_149045.3:p.Arg1034Leu
NC_000010.10:g.55719513C>A
NM_033056.3:c.3101G>T

Protein change:

R1012L

Links:

dbSNP: rs907693214

NCBI 1000 Genomes Browser:

rs907693214

Molecular consequence:

NM_001142763.2:c.3116G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142764.2:c.3101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142765.2:c.2888G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142766.2:c.3101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142767.2:c.2990G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142768.2:c.3035G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142769.3:c.3137G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142770.3:c.3101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142771.2:c.3116G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142772.2:c.3101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142773.2:c.3035G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354404.2:c.3035G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354411.2:c.3122G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354420.2:c.3101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354429.2:c.3101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001384140.1:c.3101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033056.4:c.3101G>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
SCV002050513	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 29, 2021)	germline	clinical testing	Citation Link,
SCV003457751	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 20, 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

SCV002050513

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jun 29, 2021)

germline

clinical testing

Citation Link,

SCV003457751

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 20, 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	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

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV002050513.2

#	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 (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27535533)

#	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, SCV003457751.1

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

Description

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1034 of the PCDH15 protein (p.Arg1034Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 1331229). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: Sep 29, 2024

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