NM_017934.7(PHIP):c.328C>T (p.Arg110Cys) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 8, 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:: RCV002286830.5

Allele description [Variation Report for NM_017934.7(PHIP):c.328C>T (p.Arg110Cys)]

NM_017934.7(PHIP):c.328C>T (p.Arg110Cys)

Gene:

PHIP:pleckstrin homology domain interacting protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q14.1

Genomic location:

Preferred name:

NM_017934.7(PHIP):c.328C>T (p.Arg110Cys)

HGVS:

NC_000006.12:g.79060680G>A
NG_051932.1:g.22619C>T
NM_017934.6:c.328C>T
NM_017934.7:c.328C>TMANE SELECT
NP_060404.4:p.Arg110Cys
NC_000006.11:g.79770397G>A
NC_000006.11:g.79770397G>A
NM_017934.5:c.328C>T

Protein change:

R110C

Links:

dbSNP: rs768324201

NCBI 1000 Genomes Browser:

rs768324201

Molecular consequence:

NM_017934.7:c.328C>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
SCV002576932	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 23, 2022)	germline	clinical testing	Citation Link,
SCV003273466	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 8, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29209020, 28492532
SCV004031324	Molecular Genetics laboratory, Necker Hospital	no assertion criteria provided	Pathogenic (Jan 21, 2019)	de novo	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002576932

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 23, 2022)

germline

clinical testing

Citation Link,

SCV003273466

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 8, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004031324

Molecular Genetics laboratory, Necker Hospital

no assertion criteria provided

Pathogenic
(Jan 21, 2019)

de novo

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
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

A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency.

Jansen S, Hoischen A, Coe BP, Carvill GL, Van Esch H, Bosch DGM, Andersen UA, Baker C, Bauters M, Bernier RA, van Bon BW, Claahsen-van der Grinten HL, Gecz J, Gilissen C, Grillo L, Hackett A, Kleefstra T, Koolen D, Kvarnung M, Larsen MJ, Marcelis C, McKenzie F, et al.

Eur J Hum Genet. 2018 Jan;26(1):54-63. doi: 10.1038/s41431-017-0039-5. Epub 2017 Dec 5.

PubMed [citation]

PMID:: 29209020
PMCID:: PMC5839042

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, SCV002576932.2

#	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29209020, 28263302, 27479843)

#	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, SCV003273466.2

#	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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 110 of the PHIP protein (p.Arg110Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PHIP-related conditions (PMID: 29209020). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 975951). 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 expected to disrupt PHIP protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

From Molecular Genetics laboratory, Necker Hospital, SCV004031324.1

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

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

Last Updated: Jun 29, 2024

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