VCV000048426.16 - ClinVar

NM_206933.4(USH2A):c.14031dup (p.Ala4678fs)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (6)

6 out of 6 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_206933.4(USH2A):c.14031dup (p.Ala4678fs)

Variation ID: 48426 Accession: VCV000048426.16

Type and length

Duplication, 1 bp

Location

Cytogenetic: 1q41 1: 215671073-215671074 (GRCh38) [ NCBI UCSC ] 1: 215844415-215844416 (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	Jan 30, 2015	Apr 4, 2026	Feb 17, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.14031dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Ala4678fs
NM_206933.2:c.14031_14032insA
NC_000001.11:g.215671074dup
NC_000001.10:g.215844416dup
NG_009497.2:g.757375dup

... more HGVS ... less HGVS

Protein change

A4678fs

Other names

NM_206933.2:c.14031dupA
p.Ala4678SerfsX5

Canonical SPDI

NC_000001.11:215671073:T:TT

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), exomes 0.00000

Links

ClinGen: CA262088 dbSNP: rs397517988 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		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	8088	9803

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.
Rare genetic deafness	Pathogenic (1)	criteria provided, single submitter	Nov 5, 2012	RCV000041749.5
not provided	Pathogenic (1)	criteria provided, single submitter	Feb 17, 2025	RCV001380769.9
Retinitis pigmentosa 39 Usher syndrome type 2A	Pathogenic (1)	criteria provided, single submitter	Aug 6, 2021	RCV002496661.1
Retinitis pigmentosa 39	Pathogenic (1)	criteria provided, single submitter	Nov 4, 2023	RCV003450781.1
Usher syndrome type 2A	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 18, 2024	RCV003450780.2

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.	Expand all rows Collapse all rows 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.
Pathogenic (Nov 05, 2012) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	Rare genetic deafness (Autosomal recessive inheritance)	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000065445.6 First in ClinVar: May 03, 2013 Last updated: Jan 30, 2015	Comment: show The Ala4678fs variant in USH2A has not reported in the literature nor previously identified by our laboratory. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 4678 and lead to a prematur e termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our cri teria to be classified as pathogenic (http://pcpgm.partners.org/LMM). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 1

Pathogenic (Nov 04, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Retinitis pigmentosa 39	Genome-Nilou Lab Accession: SCV004183106.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Nov 04, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Usher syndrome type 2A	Genome-Nilou Lab Accession: SCV004183107.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Aug 06, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Usher syndrome type 2A Retinitis pigmentosa 39	Fulgent Genetics, Fulgent Genetics Accession: SCV002810451.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Aug 18, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Usher syndrome type 2A	Natera, Inc. Accession: SCV007534266.1 First in ClinVar: Apr 04, 2026 Last updated: Apr 04, 2026	Publications: PubMed (1) PubMed: 25211151 Comment: show The c.14031dup variant in USH2A is a frameshift variant predicted to shift the reading frame beginning at codon 4678 and leads to a stop codon 5 codons downstream. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 25211151). Given the available evidence, this variant is classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Feb 17, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001578927.6 First in ClinVar: May 10, 2021 Last updated: Feb 15, 2026	Publications: PubMed (5) PubMed: 10729113‚ 10909849‚ 20507924‚ 25211151‚ 25649381 Comment: show This sequence change creates a premature translational stop signal (p.Ala4678Serfs*5) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 25211151). This variant is also known as c.14031_14032insA. ClinVar contains an entry for this variant (Variation ID: 48426). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

The Ala4678fs variant in USH2A has not reported in the literature nor previously identified by our laboratory. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 4678 and lead to a prematur e termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our cri teria to be classified as pathogenic (http://pcpgm.partners.org/LMM).

Comment:

The c.14031dup variant in USH2A is a frameshift variant predicted to shift the reading frame beginning at codon 4678 and leads to a stop codon 5 codons downstream. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 25211151). Given the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ala4678Serfs*5) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 25211151). This variant is also known as c.14031_14032insA. ClinVar contains an entry for this variant (Variation ID: 48426). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.	Lenassi E	European journal of human genetics : EJHG	2015	PMID: 25649381
Molecular genetics of the Usher syndrome in Lebanon: identification of 11 novel protein truncating mutations by whole exome sequencing.	Reddy R	PloS one	2014	PMID: 25211151
Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa.	McGee TL	Journal of medical genetics	2010	PMID: 20507924
Identification of novel USH2A mutations: implications for the structure of USH2A protein.	Dreyer B	European journal of human genetics : EJHG	2000	PMID: 10909849
Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa.	Weston MD	American journal of human genetics	2000	PMID: 10729113

Text-mined citations for rs397517988 ...

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 Apr 13, 2026