VCV001707882.7 - ClinVar

NM_206933.4(USH2A):c.10817T>C (p.Leu3606Pro)

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.

(4)

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.

Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_206933.4(USH2A):c.10817T>C (p.Leu3606Pro)

Variation ID: 1707882 Accession: VCV001707882.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q41 1: 215779965 (GRCh38) [ NCBI UCSC ] 1: 215953307 (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	Oct 8, 2022	Sep 16, 2024	Jun 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.10817T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Leu3606Pro	missense
NC_000001.11:g.215779965A>G
NC_000001.10:g.215953307A>G
NG_009497.2:g.648484T>C

Protein change

L3606P

Other names

Canonical SPDI

NC_000001.11:215779964: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.

Links

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.
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 31, 2022	RCV002287043.6
Retinitis pigmentosa 39	Pathogenic (1)	criteria provided, single submitter	Jul 24, 2023	RCV003471315.1
Usher syndrome	Likely pathogenic (1)	criteria provided, single submitter	Jun 11, 2024	RCV004700715.1

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 (Apr 01, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002577069.2 First in ClinVar: Oct 08, 2022 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20507924, 33535592, 27460420, 33576794) (less)
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004208375.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Aug 31, 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: SCV003524100.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 20507924‚ 27460420‚ 33576794 Comment: This variant is present in population databases (no rsID available, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to … (more) This variant is present in population databases (no rsID available, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 20507924, 27460420, 33576794). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 3606 of the USH2A protein (p.Leu3606Pro). (less)
Likely pathogenic (Jun 11, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Usher syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005204428.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Publications: PubMed (6) PubMed: 20507924‚ 27460420‚ 33576794‚ 36460718‚ 36785559‚ 33535592 Comment: Variant summary: USH2A c.10817T>C (p.Leu3606Pro) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. … (more) Variant summary: USH2A c.10817T>C (p.Leu3606Pro) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251370 control chromosomes. c.10817T>C has been reported in the literature in compound heterozygous individuals affected with Usher Syndrome or Non-syndromic Retinitis Pigmentosa (Bonnet_2016, Colombo_2021, Falsini_2021, McGee_2010, Karali_2022, Reurink_2023). However, in some cases, the second allele was not specified. These data indicate that the variant is likely to be associated with disease. 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: 27460420, 33576794, 33535592, 36460718, 20507924, 36785559). ClinVar contains an entry for this variant (Variation ID: 1707882). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20507924, 33535592, 27460420, 33576794)

Comment:

This variant is present in population databases (no rsID available, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 20507924, 27460420, 33576794). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 3606 of the USH2A protein (p.Leu3606Pro).

Comment:

Variant summary: USH2A c.10817T>C (p.Leu3606Pro) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251370 control chromosomes. c.10817T>C has been reported in the literature in compound heterozygous individuals affected with Usher Syndrome or Non-syndromic Retinitis Pigmentosa (Bonnet_2016, Colombo_2021, Falsini_2021, McGee_2010, Karali_2022, Reurink_2023). However, in some cases, the second allele was not specified. These data indicate that the variant is likely to be associated with disease. 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: 27460420, 33576794, 33535592, 36460718, 20507924, 36785559). ClinVar contains an entry for this variant (Variation ID: 1707882). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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 genome sequencing for USH2A-associated disease reveals several pathogenic deep-intronic variants that are amenable to splice correction.	Reurink J	HGG advances	2023	PMID: 36785559
Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy.	Karali M	Scientific reports	2022	PMID: 36460718
Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome.	Colombo L	Investigative ophthalmology & visual science	2021	PMID: 33576794
USH2A-Related Retinitis Pigmentosa: Staging of Disease Severity and Morpho-Functional Studies.	Falsini B	Diagnostics (Basel, Switzerland)	2021	PMID: 33535592
An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients.	Bonnet C	European journal of human genetics : EJHG	2016	PMID: 27460420
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

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_206933.4(USH2A):c.10817T>C (p.Leu3606Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...