11-17527316-C-T

Variant names:

• chr11-17527316-C-T
• rs145013633
• NM_153676.4:c.403G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_153676.4(USH1C):​c.403G>A​(p.Val135Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,612,278 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V135V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 7.57
• Publications: 7 publications found

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

USH1C Gene-Disease associations (from GenCC):

• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011645734).
• BP6: Variant 11-17527316-C-T is Benign according to our data. Variant chr11-17527316-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48015.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00232 (352/151962) while in subpopulation AMR AF = 0.00432 (66/15278). AF 95% confidence interval is 0.00348. There are 3 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_153676.4	MANE Select	c.403G>A	p.Val135Ile	missense	Exon 5 of 27	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.403G>A	p.Val135Ile	missense	Exon 5 of 21	NP_005700.2
	USH1C	NM_001440679.1		c.436G>A	p.Val146Ile	missense	Exon 5 of 22	NP_001427608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.403G>A	p.Val135Ile	missense	Exon 5 of 27	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.403G>A	p.Val135Ile	missense	Exon 5 of 21	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.403G>A	p.Val135Ile	missense	Exon 5 of 20	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 352 AN: 151844 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00433

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00227 AC: 568 AN: 250276 AF XY: 0.00245

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.000652

Gnomad FIN exome AF: 0.00141

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00249 AC: 3634 AN: 1460316 Hom.: 5 Cov.: 33 AF XY: 0.00251 AC XY: 1821 AN XY: 726534

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00280 AC: 125 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26134

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39698

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86252

European-Finnish (FIN) AF: 0.00175 AC: 91 AN: 51994

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5752

European-Non Finnish (NFE) AF: 0.00283 AC: 3147 AN: 1111904

Other (OTH) AF: 0.00237 AC: 143 AN: 60380

GnomAD4 genome AF: 0.00232 AC: 352 AN: 151962 Hom.: 3 Cov.: 30 AF XY: 0.00220 AC XY: 163 AN XY: 74246

African (AFR) AF: 0.000506 AC: 21 AN: 41462

American (AMR) AF: 0.00432 AC: 66 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5120

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4780

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00353 AC: 240 AN: 67946

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00279 Hom.: 3

Bravo AF: 0.00234

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00303 AC: 26

ExAC AF: 0.00227 AC: 275

EpiCase AF: 0.00294

EpiControl AF: 0.00450

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 1C Uncertain:1 Benign:3

Apr 11, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 18, 2021

Pars Genome Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

USH1C: BS2

Sep 18, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 18A Uncertain:1 Benign:1

Dec 26, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The USH1C c.403G>A:p.(Val135Ile) heterozygous, possibly deleterious variant was detected in an individual with sloping normal-to-moderate HL. In the same individual, two additional variants, both of them founders, have been detected in two other USH genes; one a known pathogenic variant in PCDH15, c.733C>T:p.(Arg245*), and the other, a VUS in ADGRV1, c.8308T>C:p.(Phe2770Leu), suggesting digenic or trigenic inheritance.

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Sep 13, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val135Ile in exon 5 of USH1C: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (227/66532) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145013633).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.87	L
PhyloP100		7.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.0	N
REVEL	Uncertain	0.30
Sift	Benign	0.18	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.37
MPC		0.36
ClinPred		0.028	T
GERP RS		5.1
Varity_R		0.29
gMVP		0.44
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145013633; hg19: chr11-17548863; COSMIC: COSV109404622;