NM_206933.4(USH2A):c.1663C>G (p.Leu555Val) AND not specified

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Dec 13, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000041795.14

Allele description [Variation Report for NM_206933.4(USH2A):c.1663C>G (p.Leu555Val)]

NM_206933.4(USH2A):c.1663C>G (p.Leu555Val)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.1663C>G (p.Leu555Val)

Other names:

USH2A

HGVS:

NC_000001.11:g.216292352G>C
NG_009497.2:g.136097C>G
NM_007123.6:c.1663C>G
NM_206933.4:c.1663C>GMANE SELECT
NP_009054.6:p.Leu555Val
NP_996816.3:p.Leu555Val
NC_000001.10:g.216465694G>C
NG_009497.1:g.136045C>G
NM_007123.5:c.1663C>G
NM_206933.2:c.1663C>G
NM_206933.3:c.1663C>G
O75445:p.Leu555Val
c.1663C>G

Protein change:

L555V

Links:

UniProtKB: O75445#VAR_025770; dbSNP: rs35818432

NCBI 1000 Genomes Browser:

rs35818432

Molecular consequence:

NM_007123.6:c.1663C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_206933.4:c.1663C>G - 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
SCV000065491	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (May 2, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11311042, 12525556, 21228398, 14676276, 19683999, 21738395, 24033266
SCV000341464	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely benign (May 10, 2016)	germline	clinical testing	Citation Link,
SCV004241424	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Dec 13, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 25262649, 21569298, 19683999, 30245029, 29068140, 11311042, 34781295, 36460718, 14676276 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000065491

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(May 2, 2017)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000341464

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Likely benign
(May 10, 2016)

germline

clinical testing

Citation Link,

SCV004241424

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Dec 13, 2023)

germline

clinical testing

PubMed (9)
[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	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	11	11	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa: high prevalence and phenotypic variation.

Bernal S, Ayuso C, Antiñolo G, Gimenez A, Borrego S, Trujillo MJ, Marcos I, Calaf M, Del Rio E, Baiget M.

J Med Genet. 2003 Jan;40(1):e8. No abstract available.

PubMed [citation]

PMID:: 12525556
PMCID:: PMC1735247

Carrier testing for severe childhood recessive diseases by next-generation sequencing.

Bell CJ, Dinwiddie DL, Miller NA, Hateley SL, Ganusova EE, Mudge J, Langley RJ, Zhang L, Lee CC, Schilkey FD, Sheth V, Woodward JE, Peckham HE, Schroth GP, Kim RW, Kingsmore SF.

Sci Transl Med. 2011 Jan 12;3(65):65ra4. doi: 10.1126/scitranslmed.3001756.

PubMed [citation]

PMID:: 21228398
PMCID:: PMC3740116

See all PubMed Citations (13)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000065491.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	not provided	not provided	clinical testing	PubMed (7)

Description

p.Leu555Val in exon 10 of USH2A: This variant is not expected to have clinical s ignificance because it has been identified 0.2% (24/10136) of Ashkenazi Jewish c hromosomes and in 0.2% (212/126366) of European chromosomes including 1 homozygo te by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs35818432). It has been reported in cis with another pathogenic variant in USH2A (Jaijo 2009, Vozzi 2011). A study has shown that the variant does not i mpact protein function (Bhattacharya 2004).

#	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		11	not provided	11	not provided

From Eurofins Ntd Llc (ga), SCV000341464.4

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004241424.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: USH2A c.1663C>G (p.Leu555Val) results in a conservative amino acid change located in the Laminin-type EGF domain (IPR002049) 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 0.00097 in 1613940 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00097 vs 0.011), allowing no conclusion about variant significance. c.1663C>G has been reported in the literature in individuals affected with USH2A related conditions without strong evidence for causality (examples: Leory_2001, Colombo_2022, Karali_2022). One publication reported an individual affected with Usher syndrome with this variant and a second pathogenic variant c.1841-2A>G in homozygous state, supporting a benign role for this variant (example: Jaijo_2010). Multiple reports have classified this variant as benign (examples: Shearer_2014 and Azaiez_2018). At least one publication reports experimental evidence that this variant had no effect on usherin/collagen IV binding (example: Bhattacharya_2003). The following publications have been ascertained in the context of this evaluation (PMID: 11311042, 14676276, 19683999, 21569298, 25262649, 30245029, 29068140, 34781295, 36460718). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as benign/likely benign (n=6), VUS (n=4) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly 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: Jan 19, 2025

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