VCV000060763.29 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 60763 Accession: VCV000060763.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q13.1 5: 68296301 (GRCh38) [ NCBI UCSC ] 5: 67592129 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 5, 2015	Oct 13, 2024	Jul 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_181523.3:c.1945C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_852664.1:p.Arg649Trp	missense
NM_001242466.2:c.856C>T	NP_001229395.1:p.Arg286Trp	missense
NM_181504.4:c.1135C>T	NP_852556.2:p.Arg379Trp	missense
NM_181524.2:c.1045C>T	NP_852665.1:p.Arg349Trp	missense
NC_000005.10:g.68296301C>T
NC_000005.9:g.67592129C>T
NG_012849.2:g.85546C>T
LRG_453:g.85546C>T
LRG_453t1:c.1945C>T	LRG_453p1:p.Arg649Trp
	P27986:p.Arg649Trp

... more HGVS ... less HGVS

Protein change

R649W, R379W, R286W, R349W

Other names

Canonical SPDI

NC_000005.10:68296300:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA344799 UniProtKB: P27986#VAR_070223 OMIM: 171833.0004 dbSNP: rs397515453 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PIK3R1		-	-	GRCh38 GRCh37	546	562

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
SHORT syndrome	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jul 10, 2024	RCV000054534.48
not provided	Pathogenic (1)	criteria provided, single submitter	Apr 18, 2022	RCV000414540.14
Agammaglobulinemia 7, autosomal recessive Immunodeficiency 36 SHORT syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 3, 2022	RCV000515192.17
Immunodeficiency 36	Likely pathogenic (1)	criteria provided, single submitter	Jan 1, 2016	RCV001197921.10
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jul 13, 2017	RCV001265992.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 13, 2014)	criteria provided, single submitter (Lee et al. (JAMA. 2014)) Method: clinical testing	SHORT syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	UCLA Clinical Genomics Center, UCLA Study: CES Accession: SCV000255437.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Age: 0-9 years Sex: female Testing laboratory: UCLA Clinical Genomics Center
Pathogenic (Oct 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SHORT syndrome Affected status: yes Allele origin: unknown	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV001976993.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021	Publications: PubMed (1) PubMed: 34008892 Comment: PS3, PM1, PM2, PP3, PP5
Pathogenic (Apr 18, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000490990.4 First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate that the R649W results in a decrease in phosphotyrosine and IRS1-associated PI3K activity and impaired insulin signaling (Chudasama et al., 2013; … (more) Published functional studies demonstrate that the R649W results in a decrease in phosphotyrosine and IRS1-associated PI3K activity and impaired insulin signaling (Chudasama et al., 2013; Barcena et al., 2014); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27766312, 23810382, 23810378, 23980586, 23810379, 24886349, 26974159, 27441994, 28632845, 29476696, 31829210, 31583022, 31836692, 32879144, 32602265, 34249805, 34008892, 33657699, 34026551) (less)
Pathogenic (Jul 10, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SHORT syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368188.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Criteria applied: PS3,PS4,PM2_SUP,PP3 Clinical Features: Combined immunodeficiency (present) Sex: female
Pathogenic (May 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SHORT syndrome Agammaglobulinemia 7, autosomal recessive Immunodeficiency 36 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611295.1 First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017
Likely pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 36 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368705.2 First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020	Comment: This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SHORT syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002521337.1 First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022	Publications: PubMed (2) PubMed: 23810382‚ 269880 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product … (more) The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000060763). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 23810382, 269880). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Short stature (present) , Small for gestational age (present)
Pathogenic (Jul 13, 2017)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV001444164.2 First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023	Publications: PubMed (6) PubMed: 26529633‚ 22351933‚ 23810378‚ 23810382‚ 23980586‚ 23810379 Number of individuals with the variant: 1 Clinical Features: Overlapping fingers (present) , Hypertonia (present) , Frontal bossing (present) , Triangular face (present) , Short stature (present) , Wide anterior fontanel (present) , Short … (more) Overlapping fingers (present) , Hypertonia (present) , Frontal bossing (present) , Triangular face (present) , Short stature (present) , Wide anterior fontanel (present) , Short nose (present) , Downslanted palpebral fissures (present) (less) Sex: male Ethnicity/Population group: Caucasian/Irish/French
Pathogenic (May 03, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	SHORT syndrome Immunodeficiency 36 Agammaglobulinemia 7, autosomal recessive Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000827309.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (10) PubMed: 28492532‚ 23810378‚ 23810379‚ 23810382‚ 23980586‚ 24886349‚ 25326637‚ 27766312‚ 26974159‚ 28632845 Comment: 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 … (more) 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. (less)
Pathogenic (Jul 11, 2013)	no assertion criteria provided Method: literature only	SHORT SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000083012.2 First in ClinVar: Aug 28, 2013 Last updated: Aug 22, 2016	Publications: PubMed (8) PubMed: 11135494‚ 23810378‚ 6407320‚ 12514365‚ 23810379‚ 8574420‚ 18384141‚ 23810382 Comment on evidence: In 5 patients from 4 families with SHORT syndrome (269880), including a patient previously reported by Bonnel et al. (2000), Thauvin-Robinet et al. (2013) identified … (more) In 5 patients from 4 families with SHORT syndrome (269880), including a patient previously reported by Bonnel et al. (2000), Thauvin-Robinet et al. (2013) identified heterozygosity for a c.1945C-T transition at chr5:67,592,129 (GRCh37) in the PIK3R1 gene, resulting in an arg649-to-trp (R649W) substitution at a highly conserved residue in the cSH2 domain. In the 1 family for which parental DNA was available, the mutation was shown to be de novo. Thauvin-Robinet et al. (2013) noted that the c.1945C-T mutation occurred within the context of a CpG dinucleotide, which might explain its recurrence. In affected members of a 3-generation Norwegian family with SHORT syndrome, originally described by Aarskog et al. (1983), and a German mother and son with SHORT syndrome, originally reported by Koenig et al. (2003), Chudasama et al. (2013) identified heterozygosity for the R649W missense mutation in the PIK3R1 gene. The mutation was not found in 340 Norwegian controls. Haplotype analysis showed that the mutations resided on different backgrounds in the 2 families, indicating that they stemmed from 2 independent mutational events. Analysis of patient fibroblasts and reconstituted Pik3r1-knockout preadipocytes demonstrated impaired interaction between p85-alpha and IRS1 (147545) and reduced AKT (see 164730)-mediated insulin signaling. In a mother and 2 sons from an English family with SHORT syndrome, originally reported by Bankier et al. (1995) and restudied by Reardon and Temple (2008), and in an unrelated male patient, Dyment et al. (2013) identified heterozygosity for the R649W mutation in the PIK3R1 gene. (less)
Pathogenic (Jul 18, 2018)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	SHORT syndrome Affected status: yes Allele origin: de novo	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals Accession: SCV000898155.1 First in ClinVar: Apr 22, 2019 Last updated: Apr 22, 2019
Pathogenic (Jun 09, 2021)	no assertion criteria provided Method: clinical testing	SHORT syndrome Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002072027.3 First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022	Comment: DNA sequence analysis of the PIK3R1 gene demonstrated a sequence change, c.1945C>T, in exon 15 that results in an amino acid change, p.Arg649Trp. This sequence … (more) DNA sequence analysis of the PIK3R1 gene demonstrated a sequence change, c.1945C>T, in exon 15 that results in an amino acid change, p.Arg649Trp. This sequence change has not been described in population databases (dbSNP rs397515453). The p.Arg649Trp change affects a highly conserved amino acid residue located in a domain of the PIK3R1 protein that is known to be functional. The p.Arg649Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change is a well-described missense variant that has previously been reported in multiple individuals with SHORT syndrome (PMID: 23810382, 23810379, 31829210, 29476696, 27766312, 32879144, 23980586, 32602265). Additionally, experimental studies have shown that this missense change impacts the function of the PIK3R1 protein (PMID: 27766312, 28632845, 23810379, 26974159). (less)
not provided (-)	no classification provided Method: literature only	SHORT syndrome Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000148015.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 23810378
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Comment:

Published functional studies demonstrate that the R649W results in a decrease in phosphotyrosine and IRS1-associated PI3K activity and impaired insulin signaling (Chudasama et al., 2013; Barcena et al., 2014); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27766312, 23810382, 23810378, 23980586, 23810379, 24886349, 26974159, 27441994, 28632845, 29476696, 31829210, 31583022, 31836692, 32879144, 32602265, 34249805, 34008892, 33657699, 34026551)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000060763). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 23810382, 269880). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

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.

Comment:

DNA sequence analysis of the PIK3R1 gene demonstrated a sequence change, c.1945C>T, in exon 15 that results in an amino acid change, p.Arg649Trp. This sequence change has not been described in population databases (dbSNP rs397515453). The p.Arg649Trp change affects a highly conserved amino acid residue located in a domain of the PIK3R1 protein that is known to be functional. The p.Arg649Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change is a well-described missense variant that has previously been reported in multiple individuals with SHORT syndrome (PMID: 23810382, 23810379, 31829210, 29476696, 27766312, 32879144, 23980586, 32602265). Additionally, experimental studies have shown that this missense change impacts the function of the PIK3R1 protein (PMID: 27766312, 28632845, 23810379, 26974159).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders.	Marinakis NM	American journal of medical genetics. Part A	2021	PMID: 34008892
SHORT Syndrome.	Adam MP	-	2020	PMID: 24830046
Iris Malformation and Anterior Segment Dysgenesis in Mice and Humans With a Mutation in PI 3-Kinase.	Solheim MH	Investigative ophthalmology & visual science	2017	PMID: 28632845
Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.	Huang-Doran I	JCI insight	2016	PMID: 27766312
PI3-kinase mutation linked to insulin and growth factor resistance in vivo.	Winnay JN	The Journal of clinical investigation	2016	PMID: 26974159
De novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly.	Kuhlen M	Clinical immunology (Orlando, Fla.)	2016	PMID: 26529633
Clinical exome sequencing for genetic identification of rare Mendelian disorders.	Lee H	JAMA	2014	PMID: 25326637
Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome.	Bárcena C	BMC medical genetics	2014	PMID: 24886349
PIK3R1 mutations in SHORT syndrome.	Schroeder C	Clinical genetics	2014	PMID: 23980586
Mutations in PIK3R1 cause SHORT syndrome.	Dyment DA	American journal of human genetics	2013	PMID: 23810382
SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling.	Chudasama KK	American journal of human genetics	2013	PMID: 23810379
PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.	Thauvin-Robinet C	American journal of human genetics	2013	PMID: 23810378
Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K.	Conley ME	The Journal of experimental medicine	2012	PMID: 22351933
Nephrocalcinosis and disordered calcium metabolism in two children with SHORT syndrome.	Reardon W	American journal of medical genetics. Part A	2008	PMID: 18384141
SHORT syndrome.	Koenig R	Clinical dysmorphology	2003	PMID: 12514365
SHORT syndrome: a case with high hyperopia and astigmatism.	Bonnel S	Ophthalmic genetics	2000	PMID: 11135494
Absent iris stroma, narrow body build and small facial bones: a new association or variant of SHORT syndrome?	Bankier A	Clinical dysmorphology	1995	PMID: 8574420
Autosomal dominant partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes.	Aarskog D	American journal of medical genetics	1983	PMID: 6407320
A new desensitizing dentifrice: preliminary report.	Zinner DD	Journal of the American Dental Association (1939)	1977	PMID: 269880
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Text-mined citations for rs397515453 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397515453 ...