NM_181523.3(PIK3R1):c.1945C>T (p.Arg649Trp) AND multiple conditions

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 3, 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:: RCV000515192.17

Allele description

NM_181523.3(PIK3R1):c.1945C>T (p.Arg649Trp)

Gene:

PIK3R1:phosphoinositide-3-kinase regulatory subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q13.1

Genomic location:

Preferred name:

NM_181523.3(PIK3R1):c.1945C>T (p.Arg649Trp)

HGVS:

NC_000005.10:g.68296301C>T
NG_012849.2:g.85546C>T
NM_001242466.2:c.856C>T
NM_181504.4:c.1135C>T
NM_181523.3:c.1945C>TMANE SELECT
NM_181524.2:c.1045C>T
NP_001229395.1:p.Arg286Trp
NP_852556.2:p.Arg379Trp
NP_852664.1:p.Arg649Trp
NP_852664.1:p.Arg649Trp
NP_852665.1:p.Arg349Trp
LRG_453t1:c.1945C>T
LRG_453:g.85546C>T
LRG_453p1:p.Arg649Trp
NC_000005.9:g.67592129C>T
NM_181523.1:c.1945C>T
NM_181523.2:c.1945C>T
P27986:p.Arg649Trp

Protein change:

R286W; ARG649TRP

Links:

UniProtKB: P27986#VAR_070223; OMIM: 171833.0004; dbSNP: rs397515453

NCBI 1000 Genomes Browser:

rs397515453

Molecular consequence:

NM_001242466.2:c.856C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181504.4:c.1135C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181523.3:c.1945C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181524.2:c.1045C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: SHORT syndrome
Synonyms:: SHORT STATURE, HYPEREXTENSIBILITY, HERNIA, OCULAR DEPRESSION, RIEGER ANOMALY, AND TEETHING DELAY; Stature, Hyperextensibility of joints or Hernia (inguinal), Ocular depression, Rieger anomaly and Teething delay; LIPODYSTROPHY, PARTIAL, WITH RIEGER ANOMALY AND SHORT STATURE
Identifiers:: MONDO: MONDO:0010026; MedGen: C0878684; Orphanet: 3163; OMIM: 269880

Name:: Agammaglobulinemia 7, autosomal recessive (AGM7)
Synonyms:: AGAMMAGLOBULINEMIA, AUTOSOMAL RECESSIVE, DUE TO PIK3R1 DEFECT
Identifiers:: MONDO: MONDO:0014083; MedGen: C3554689; OMIM: 615214

Name:: Immunodeficiency 36 (IMD36)
Synonyms:: IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION
Identifiers:: MONDO: MONDO:0014453; MedGen: C4014934; Orphanet: 397596; OMIM: 616005

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000611295	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 18, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000827309	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 3, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 23810378, 23810382, 23980586, 24886349, 25326637, 23810379, 26974159, 27766312, 28632845, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000611295

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 18, 2017)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000827309

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 3, 2022)

germline

clinical testing

PubMed (10)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.

Thauvin-Robinet C, Auclair M, Duplomb L, Caron-Debarle M, Avila M, St-Onge J, Le Merrer M, Le Luyer B, Héron D, Mathieu-Dramard M, Bitoun P, Petit JM, Odent S, Amiel J, Picot D, Carmignac V, Thevenon J, Callier P, Laville M, Reznik Y, Fagour C, Nunes ML, et al.

Am J Hum Genet. 2013 Jul 11;93(1):141-9. doi: 10.1016/j.ajhg.2013.05.019. Epub 2013 Jun 27.

PubMed [citation]

PMID:: 23810378
PMCID:: PMC3710759

See all PubMed Citations (11)

Details of each submission

From Fulgent Genetics, Fulgent Genetics, SCV000611295.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000827309.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 649 of the PIK3R1 protein (p.Arg649Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SHORT syndrome (PMID: 23810378, 23810379, 23810382, 23980586, 24886349, 25326637, 27766312). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 60763). 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 PIK3R1 protein function. Experimental studies have shown that this missense change affects PIK3R1 function (PMID: 23810379, 26974159, 27766312, 28632845). 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: Nov 24, 2024

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