NM_206933.4(USH2A):c.8431C>A (p.Pro2811Thr) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 4, 2024
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:: RCV000041927.8

Allele description [Variation Report for NM_206933.4(USH2A):c.8431C>A (p.Pro2811Thr)]

NM_206933.4(USH2A):c.8431C>A (p.Pro2811Thr)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.8431C>A (p.Pro2811Thr)

HGVS:

NC_000001.11:g.215878891G>T
NG_009497.2:g.549558C>A
NM_206933.4:c.8431C>AMANE SELECT
NP_996816.3:p.Pro2811Thr
NC_000001.10:g.216052233G>T
NG_009497.1:g.549506C>A
NM_206933.2:c.8431C>A
c.8431C>A

Protein change:

P2811T

Links:

dbSNP: rs111033529

NCBI 1000 Genomes Browser:

rs111033529

Molecular consequence:

NM_206933.4:c.8431C>A - 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
SCV000065623	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Aug 21, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28041643, 28838317, 24033266
SCV004804170	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jan 4, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 28041643, 29625443, 28838317, 35266249, 33269433, 28281779 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000065623

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Aug 21, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004804170

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jan 4, 2024)

germline

clinical testing

PubMed (6)
[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	not provided	7	3	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

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 Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, Megy K, Grozeva D, Dewhurst E, Malka S, Plagnol V, Penkett C, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, et al.

Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.

PubMed [citation]

PMID:: 28041643
PMCID:: PMC5223092

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000065623.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (3)

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Pro2811Thr va riant in USH2A has been reported by our laboratory in a family with hearing loss , however, it has been identified in 0.24% (39/16508) of South Asian chromosomes , including 2 homozygotes, by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs111033529). Computational prediction tools and con servation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, wh ile the clinical significance of the p.Pro2811Thr variant is uncertain, the freq uency data suggests it is more likely to be 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		7	not provided	3	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004804170.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: USH2A c.8431C>A (p.Pro2811Thr) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251274 control chromosomes, predominantly at a frequency of 0.0022 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00029 vs 0.011), allowing no conclusion about variant significance. c.8431C>A has been reported in the literature in individuals affected with Usher Syndrome, reported as a VUS with unknown genotype (e.g. Hufnagel_2022) or as a compound heterozygous genotype, without evidence of causality in a single-gene testing setting (e.g. Sun_2018), in individuals affected with retinitis pigmentosa as a compound heterozygous genotype in settings of multi-gene panel testing (e.g. Wang_2017a) or WGS or WES testing with two additional USH2A variants reported (e.g. Carss_2017), or in compound heterozygous individuals affected with hearing loss with the second variant classified as benign (e.g.Wang_2017b) or other variants present in multiple genes (e.g. Park_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28041643, 35266249, 33269433, 29625443, 28838317, 28281779). ClinVar contains an entry for this variant (Variation ID: 48601). 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: Mar 30, 2024

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