VCV000005149.32 - ClinVar

NM_153676.4(USH1C):c.388G>A (p.Val130Ile)

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.

(11)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_153676.4(USH1C):c.388G>A (p.Val130Ile)

Variation ID: 5149 Accession: VCV000005149.32

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.1 11: 17527331 (GRCh38) [ NCBI UCSC ] 11: 17548878 (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	Jul 25, 2015	Sep 29, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_153676.4:c.388G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_710142.1:p.Val130Ile	missense
NM_005709.4:c.388G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005700.2:p.Val130Ile	missense
NM_001297764.2:c.388G>A	NP_001284693.1:p.Val130Ile	missense
NR_123738.2:n.497G>A		non-coding transcript variant
NC_000011.10:g.17527331C>T
NC_000011.9:g.17548878C>T
NG_011883.2:g.22086G>A

... more HGVS ... less HGVS

Protein change

V130I

Other names

Canonical SPDI

NC_000011.10:17527330:C:T

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.

0.01298 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00317

Exome Aggregation Consortium (ExAC) 0.00408

1000 Genomes Project 0.01298

The Genome Aggregation Database (gnomAD) 0.01363

1000 Genomes Project 30x 0.01405

Trans-Omics for Precision Medicine (TOPMed) 0.01461

Links

ClinGen: CA142377 OMIM: 605242.0010 dbSNP: rs55843567 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.
USH1C		-	-	GRCh38 GRCh37	1378	1402

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 1C	Benign (3)	criteria provided, single submitter	Apr 27, 2017	RCV000005456.18
not specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	May 3, 2022	RCV000041291.20
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000972120.22
Autosomal recessive nonsyndromic hearing loss 18A Usher syndrome type 1 Usher syndrome type 1C	Benign (1)	criteria provided, single submitter	May 2, 2022	RCV002496267.8

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.
Benign (Jul 10, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000332784.4 First in ClinVar: Dec 06, 2016 Last updated: Apr 09, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH1C Number of individuals with the variant: 1 Sex: mixed
Benign (Apr 06, 2010)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000064982.6 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Publications: PubMed (1) PubMed: 12702164 Number of individuals with the variant: 29
Benign (Apr 17, 2020)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001472060.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005316564.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Mar 12, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000730518.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Usher syndrome type 1C Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001262249.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 20142502‚ 25262649‚ 12702164 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
Likely benign (May 03, 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: SCV002548391.1 First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022
Benign (May 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 1 Usher syndrome type 1C Autosomal recessive nonsyndromic hearing loss 18A Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002805319.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Jan 31, 2024)	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: SCV001119814.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Uncertain significance (Oct 02, 2014)	no assertion criteria provided Method: literature only	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025638.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 29, 2019	Publications: PubMed (2) PubMed: 25262649‚ 12702164 Comment on evidence: This variant, formerly titled USHER SYNDROME, TYPE IC, has been reclassified based on the findings of Shearer et al. (2014). In a U.K. patient with … (more) This variant, formerly titled USHER SYNDROME, TYPE IC, has been reclassified based on the findings of Shearer et al. (2014). In a U.K. patient with type I Usher syndrome (USH1C; 276904), Blaydon et al. (2003) identified a 388G-A transition in exon 5 of the USH1C gene, resulting in a val130-to-ile (V130I) mutation in the first PDZ domain of the protein. No mutation was identified on the other allele. Based on allele frequency in 8,595 controls from 12 populations (maximum minor allele frequency = 0.0600), Shearer et al. (2014) recategorized the V130I variant in the USH1C gene as benign. (less)
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Usher syndrome type 1C Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001456085.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

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
Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants.	Shearer AE	American journal of human genetics	2014	PMID: 25262649
The structure of the harmonin/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins.	Yan J	Proceedings of the National Academy of Sciences of the United States of America	2010	PMID: 20142502
The contribution of USH1C mutations to syndromic and non-syndromic deafness in the UK.	Blaydon DC	Clinical genetics	2003	PMID: 12702164
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH1C	-	-	-	-

Text-mined citations for rs55843567 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_153676.4(USH1C):c.388G>A (p.Val130Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs55843567 ...