NM_206933.4(USH2A):c.15496A>G (p.Ile5166Val) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 2, 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:: RCV000041788.13

Allele description [Variation Report for NM_206933.4(USH2A):c.15496A>G (p.Ile5166Val)]

NM_206933.4(USH2A):c.15496A>G (p.Ile5166Val)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.15496A>G (p.Ile5166Val)

HGVS:

NC_000001.11:g.215628837T>C
NG_009497.2:g.799612A>G
NM_206933.4:c.15496A>GMANE SELECT
NP_996816.3:p.Ile5166Val
NC_000001.10:g.215802179T>C
NG_009497.1:g.799560A>G
NM_206933.2:c.15496A>G
NM_206933.3:c.15496A>G
c.15496A>G

Protein change:

I5166V

Links:

dbSNP: rs111033419

NCBI 1000 Genomes Browser:

rs111033419

Molecular consequence:

NM_206933.4:c.15496A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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PLS3 plastin 3 [Homo sapiens]
PLS3 plastin 3 [Homo sapiens]
Gene ID:5358

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000065484	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (May 15, 2009)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002599043	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Sep 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26969326, 27460420, 32531858, 34638692 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000065484

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(May 15, 2009)

germline

clinical testing

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

SCV002599043

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Sep 2, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss.

Sloan-Heggen CM, Bierer AO, Shearer AE, Kolbe DL, Nishimura CJ, Frees KL, Ephraim SS, Shibata SB, Booth KT, Campbell CA, Ranum PT, Weaver AE, Black-Ziegelbein EA, Wang D, Azaiez H, Smith RJH.

Hum Genet. 2016 Apr;135(4):441-450. doi: 10.1007/s00439-016-1648-8. Epub 2016 Mar 11.

PubMed [citation]

PMID:: 26969326
PMCID:: PMC4796320

See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000065484.6

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002599043.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: USH2A c.15496A>G (p.Ile5166Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 282882 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (4.2e-05 vs 0.011), allowing no conclusion about variant significance. c.15496A>G has been reported in the literature as a biallelic genotype in individuals affected with Usher Syndrome (Sloan-Heggen_2016, Bonnet_2016, Weisschuh_2020, Fakin_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly 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 10, 2024

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