VCV000557599.12 - ClinVar

NM_206933.4(USH2A):c.14017T>C (p.Tyr4673His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_206933.4(USH2A):c.14017T>C (p.Tyr4673His)

Variation ID: 557599 Accession: VCV000557599.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q41 1: 215671088 (GRCh38) [ NCBI UCSC ] 1: 215844430 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 5, 2018	Oct 8, 2024	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.14017T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Tyr4673His	missense
NC_000001.11:g.215671088A>G
NC_000001.10:g.215844430A>G
NG_009497.2:g.757361T>C

Protein change

Y4673H

Other names

Canonical SPDI

NC_000001.11:215671087:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

dbSNP: rs1040917329 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
USH2A		-	-	GRCh38 GRCh37	7080	8575

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Usher syndrome type 2A	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 4, 2023	RCV001810480.11
not specified	Uncertain significance (1)	criteria provided, single submitter	Jun 2, 2022	RCV002271562.8
not provided	Uncertain significance (1)	criteria provided, single submitter	Mar 29, 2022	RCV002531342.9
Retinitis pigmentosa 39	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV003453366.4
Retinal dystrophy	Uncertain significance (1)	criteria provided, single submitter	Oct 1, 2023	RCV003889962.1
USH2A-related disorder	Uncertain significance (1)	no assertion criteria provided	Aug 27, 2024	RCV004732997.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jun 02, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002556308.1 First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022	Publications: PubMed (10) PubMed: 23967202‚ 31054281‚ 26927203‚ 31541171‚ 32675063‚ 24853665‚ 33124170‚ 25373420‚ 33691693‚ 26992781 Comment: Variant summary: USH2A c.14017T>C (p.Tyr4673His) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign … (more) Variant summary: USH2A c.14017T>C (p.Tyr4673His) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251322 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.14017T>C has been reported in the literature in individuals affected with deafness, Retinitis Pigmentosa, or retinal degeneration. 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Oct 01, 2021)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021)) Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV002060331.2 First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022	Publications: PubMed (5) PubMed: 26992781‚ 25373420‚ 26927203‚ 23967202‚ 24853665 Comment: NM_206933.2(USH2A):c.14017T>C(Y4673H) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. Y4673H has been observed in cases with … (more) NM_206933.2(USH2A):c.14017T>C(Y4673H) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. Y4673H has been observed in cases with relevant disease (PMID: 26992781, 25373420, 24853665, 26927203, 23967202). Functional assessments of this variant are not available in the literature. Y4673H has been observed in population frequency databases (gnomAD: EAS 0.02%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.14017T>C(Y4673H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
Uncertain significance (Mar 29, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003523650.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (8) PubMed: 25373420‚ 26992781‚ 30948794‚ 31054281‚ 32188678‚ 32675063‚ 32893482‚ 33090715 Comment: This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 4673 of the USH2A protein (p.Tyr4673His). … (more) This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 4673 of the USH2A protein (p.Tyr4673His). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 25373420, 26992781, 30948794, 31054281, 32188678, 32675063, 32893482, 33090715). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 557599). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Nov 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004183108.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Uncertain significance (Nov 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004183109.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Uncertain significance (Oct 01, 2023)	criteria provided, single submitter (Submitter's publication) Method: research	Retinal dystrophy Affected status: yes Allele origin: germline	Dept Of Ophthalmology, Nagoya University Accession: SCV004707222.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024
Uncertain significance (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004207703.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Aug 27, 2024)	no assertion criteria provided Method: clinical testing	USH2A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005347465.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The USH2A c.14017T>C variant is predicted to result in the amino acid substitution p.Tyr4673His. This variant has been reported in multiple individuals with symptoms of … (more) The USH2A c.14017T>C variant is predicted to result in the amino acid substitution p.Tyr4673His. This variant has been reported in multiple individuals with symptoms of Usher syndrome (see for example, Miyagawa et al. 2013. PubMed ID: 23967202; Chen et al. 2020. PubMed ID: 32893482; Liu et al. 2020. PubMed ID: 33090715). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

Variant summary: USH2A c.14017T>C (p.Tyr4673His) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251322 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.14017T>C has been reported in the literature in individuals affected with deafness, Retinitis Pigmentosa, or retinal degeneration. 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

NM_206933.2(USH2A):c.14017T>C(Y4673H) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. Y4673H has been observed in cases with relevant disease (PMID: 26992781, 25373420, 24853665, 26927203, 23967202). Functional assessments of this variant are not available in the literature. Y4673H has been observed in population frequency databases (gnomAD: EAS 0.02%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.14017T>C(Y4673H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 4673 of the USH2A protein (p.Tyr4673His). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 25373420, 26992781, 30948794, 31054281, 32188678, 32675063, 32893482, 33090715). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 557599). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The USH2A c.14017T>C variant is predicted to result in the amino acid substitution p.Tyr4673His. This variant has been reported in multiple individuals with symptoms of Usher syndrome (see for example, Miyagawa et al. 2013. PubMed ID: 23967202; Chen et al. 2020. PubMed ID: 32893482; Liu et al. 2020. PubMed ID: 33090715). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Whole-exome sequencing in 168 Korean patients with inherited retinal degeneration.	Ma DJ	BMC medical genomics	2021	PMID: 33691693
Correlation between Genotype and Phenotype in 69 Chinese Patients with USH2A Mutations: A comparative study of the patients with Usher Syndrome and Nonsyndromic Retinitis Pigmentosa.	Meng X	Acta ophthalmologica	2021	PMID: 33124170
Molecular diagnosis based on comprehensive genetic testing in 800 Chinese families with non-syndromic inherited retinal dystrophies.	Liu X	Clinical & experimental ophthalmology	2021	PMID: 33090715
USH2A variants in Chinese patients with Usher syndrome type II and non-syndromic retinitis pigmentosa.	Zhu T	The British journal of ophthalmology	2021	PMID: 32675063
Prevalence and genetic-phenotypic characteristics of patients with USH2A mutations in a large cohort of Chinese patients with inherited retinal disease.	Gao FJ	The British journal of ophthalmology	2021	PMID: 32188678
Multimodal imaging and genetic characteristics of Chinese patients with USH2A-associated nonsyndromic retinitis pigmentosa.	Chen C	Molecular genetics & genomic medicine	2020	PMID: 32893482
Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls.	Yuan Y	European journal of human genetics : EJHG	2020	PMID: 31541171
Genetic and Clinical Findings in a Large Cohort of Chinese Patients with Suspected Retinitis Pigmentosa.	Gao FJ	Ophthalmology	2019	PMID: 31054281
Whole exome sequencing identifies novel USH2A mutations and confirms Usher syndrome 2 diagnosis in Chinese retinitis pigmentosa patients.	Ng TK	Scientific reports	2019	PMID: 30948794
Molecular genetics of cone-rod dystrophy in Chinese patients: New data from 61 probands and mutation overview of 163 probands.	Huang L	Experimental eye research	2016	PMID: 26992781
Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa.	Pierrache LH	Ophthalmology	2016	PMID: 26927203
Genetic testing for sporadic hearing loss using targeted massively parallel sequencing identifies 10 novel mutations.	Gu X	Clinical genetics	2015	PMID: 24853665
Exploration of molecular genetic etiology for Korean cochlear implantees with severe to profound hearing loss and its implication.	Park JH	Orphanet journal of rare diseases	2014	PMID: 25373420
Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients.	Miyagawa M	PloS one	2013	PMID: 23967202
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Text-mined citations for rs1040917329 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_206933.4(USH2A):c.14017T>C (p.Tyr4673His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1040917329 ...