NM_000212.3(ITGB3):c.557C>T (p.Pro186Leu) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 14, 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:: RCV001816941.5

Allele description [Variation Report for NM_000212.3(ITGB3):c.557C>T (p.Pro186Leu)]

NM_000212.3(ITGB3):c.557C>T (p.Pro186Leu)

Gene:

ITGB3:integrin subunit beta 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.32

Genomic location:

Preferred name:

NM_000212.3(ITGB3):c.557C>T (p.Pro186Leu)

Other names:

NM_000212.3(ITGB3):c.557C>T; p.Pro186Leu

HGVS:

NC_000017.11:g.47284638C>T
NG_008332.2:g.35797C>T
NM_000212.3:c.557C>TMANE SELECT
NP_000203.2:p.Pro186Leu
LRG_481t1:c.557C>T
LRG_481:g.35797C>T
NC_000017.10:g.45362004C>T
NC_000017.10:g.45362004C>T
NM_000212.2:c.557C>T

Protein change:

P186L

Links:

dbSNP: rs61736876

NCBI 1000 Genomes Browser:

rs61736876

Molecular consequence:

NM_000212.3:c.557C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002066536	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 4, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002555862	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jun 14, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002066536

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 4, 2021)

germline

clinical testing

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

SCV002555862

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jun 14, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	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

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

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002066536.1

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

Description

DNA sequence analysis of the ITGB3 gene demonstrated a sequence change, c.557C>T, in exon 4 that results in an amino acid change, p.Pro186Leu. This sequence change does not appear to have been previously described in individuals with ITGB3-related disorders and has been described in the gnomAD database with a relatively high frequency of 0.71% in the African sub-population (dbSNP rs61736876). The p.Pro186Leu change affects a highly conserved amino acid residue located in a domain of the ITGB3 protein that is known to be functional. The p.Pro186Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro186Leu change remains unknown at this time.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002555862.1

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

Description

Variant summary: ITGB3 c.557C>T (p.Pro186Leu) results in a non-conservative amino acid change located in the Integrin beta subunit, VWA domain (IPR002369) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 150904 control chromosomes in the gnomAD database (v3.1.2), including 3 homozygotes. To our knowledge, no occurrence of c.557C>T in individuals affected with Glanzmann Thrombasthenia 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as 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: Oct 13, 2024

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