NM_206933.4(USH2A):c.7685T>C (p.Val2562Ala) AND not specified

Germline classification:: Benign (4 submissions)
Last evaluated:: Jan 15, 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:: RCV000041915.13

Allele description [Variation Report for NM_206933.4(USH2A):c.7685T>C (p.Val2562Ala)]

NM_206933.4(USH2A):c.7685T>C (p.Val2562Ala)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.7685T>C (p.Val2562Ala)

HGVS:

NC_000001.11:g.215888964A>G
NG_009497.2:g.539485T>C
NM_206933.4:c.7685T>CMANE SELECT
NP_996816.3:p.Val2562Ala
NC_000001.10:g.216062306A>G
NG_009497.1:g.539433T>C
NM_206933.2:c.7685T>C
NM_206933.3:c.7685T>C
O75445:p.Val2562Ala
c.7685T>C

Protein change:

V2562A

Links:

UniProtKB: O75445#VAR_054592; dbSNP: rs56385601

NCBI 1000 Genomes Browser:

rs56385601

Molecular consequence:

NM_206933.4:c.7685T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000065611	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Benign (Jan 17, 2011)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18273898, 20052763, 19683999, 24033266
SCV000230559	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Benign (Feb 5, 2015)	germline	clinical testing	Citation Link,
SCV001477202	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Benign (Sep 30, 2019)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19683999, 18273898, 20052763, 26467025
SCV002074296	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Jan 15, 2022)	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	not provided	34	34	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	3	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

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

Microarray-based mutation analysis of 183 Spanish families with Usher syndrome.

Jaijo T, Aller E, García-García G, Aparisi MJ, Bernal S, Avila-Fernández A, Barragán I, Baiget M, Ayuso C, Antiñolo G, Díaz-Llopis M, Külm M, Beneyto M, Nájera C, Millán JM.

Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1311-7. doi: 10.1167/iovs.09-4085. Epub 2009 Aug 13.

PubMed [citation]

PMID:: 19683999

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000065611.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	34	not provided	not provided	clinical testing	PubMed (4)

Description

Val2562Ala in exon 41 of USH2A: This variant has been reported in nine individua ls with a clinical diagnosis of Usher Syndrome types 1, 2 or 3 (Dreyer 2008, Jai jo 2009). However, several of these individuals already had other explanations f or their Usher syndrome (Jaijo 2009). In addition, this amino acid is not highly conserved acroos evolution, with the mouse and rat having an alanine at positio n 2562. In addition, this variant is listed in dbSNP (rs56385601 - no frequency data available) and has been identified in 6/278 (2.2%) probands tested by our l aboratory, none of whom had a variant on their second USH2A allele. In summary, this variant meets our criteria to be classified as benign.

#	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		34	not provided	34	not provided

From Eurofins Ntd Llc (ga), SCV000230559.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

#	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		3	not provided	not provided	not provided

From Athena Diagnostics, SCV001477202.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002074296.1

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

Description

Variant summary: USH2A c.7685T>C (p.Val2562Ala) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 251140 control chromosomes, predominantly at a frequency of 0.0095 within the Non-Finnish European subpopulation in the gnomAD database, including 12 homozygotes. This frequency is close to that estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0065 vs 0.011), supporting a neutral outcome. Although reported frequently in the literature, to our knowledge, no occurrence of c.7685T>C in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one report listed this variant along with two other pathogenic alleles in an individual with Usher syndrome, supporting a benign outcome (example, Hagag_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

#	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 20, 2024

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