NM_001366722.1(GRIP1):c.1756A>C (p.Ile586Leu) AND Fraser syndrome 3

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 29, 2018
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:: RCV000678296.7

Allele description [Variation Report for NM_001366722.1(GRIP1):c.1756A>C (p.Ile586Leu)]

NM_001366722.1(GRIP1):c.1756A>C (p.Ile586Leu)

Gene:

GRIP1:glutamate receptor interacting protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q14.3

Genomic location:

Preferred name:

NM_001366722.1(GRIP1):c.1756A>C (p.Ile586Leu)

HGVS:

NC_000012.12:g.66432560T>G
NG_021400.2:g.641706A>C
NM_001178074.2:c.1600A>C
NM_001366722.1:c.1756A>CMANE SELECT
NM_001366723.1:c.1675A>C
NM_001366724.1:c.1678A>C
NM_021150.4:c.1600A>C
NP_001171545.1:p.Ile534Leu
NP_001353651.1:p.Ile586Leu
NP_001353652.1:p.Ile559Leu
NP_001353653.1:p.Ile560Leu
NP_066973.2:p.Ile534Leu
NC_000012.11:g.66826340T>G
NG_021400.1:g.251586A>C
NM_021150.3:c.1600A>C

Protein change:

I534L

Links:

dbSNP: rs189438534

NCBI 1000 Genomes Browser:

rs189438534

Molecular consequence:

NM_001178074.2:c.1600A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001366722.1:c.1756A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001366723.1:c.1675A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001366724.1:c.1678A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_021150.4:c.1600A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Fraser syndrome 3
Identifiers:: MONDO: MONDO:0054739; MedGen: C4540040; OMIM: 617667

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000804354	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 29, 2018)	maternal	provider interpretation, clinical testing	PubMed (2) [See all records that cite these PMIDs] 21383172, 25741868
SCV001267517	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000804354

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 29, 2018)

maternal

provider interpretation, clinical testing

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

SCV001267517

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

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

Citation Link

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	maternal	no	1	not provided	not provided	1	not provided	clinical testing, provider interpretation

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

Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism.

Mejias R, Adamczyk A, Anggono V, Niranjan T, Thomas GM, Sharma K, Skinner C, Schwartz CE, Stevenson RE, Fallin MD, Kaufmann W, Pletnikov M, Valle D, Huganir RL, Wang T.

Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4920-5. doi: 10.1073/pnas.1102233108. Epub 2011 Mar 7.

PubMed [citation]

PMID:: 21383172
PMCID:: PMC3064362

Details of each submission

From Geisinger Autism and Developmental Medicine Institute, Geisinger Health System, SCV000804354.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	PubMed (2)
2	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

This is a 12 year old male with intellectual disability, autism spectrum disorder, mild hyptonia, hyperkinesis, and sleep problems. He has no history of seizures. This p.Ile534Leu variant is present in gnomAD non-Finnish European population at 0.22%. Computational prediction models are inconsistent. This patient does not have congenital anomalies that would be consistent with Fraser syndrome. This variant has been reported as a possible modifier of autism (Mejias, 2011) using alternate nomenclature (I586L). Whole exome sequencing identified a likely pathogenic, de novo variant in SCN2A and 1 additional variant of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	maternal	no	1	not provided	not provided		1	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001267517.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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: Apr 15, 2024

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