11-17531234-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 5P and 13B. PM1PM5PP3BP4_StrongBP6BS1BS2

The NM_153676.4(USH1C):c.307C>T(p.Arg103Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00053 in 1,614,136 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 7 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 4.76

Publications

2 publications found

Variant links:

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

USH1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_153676.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-17531233-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, Cadd, Dann, FATHMM_MKL, M_CAP, PrimateAI, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.022108346).

BP6

Variant 11-17531234-G-A is Benign according to our data. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013. Variant chr11-17531234-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48013.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00021 (32/152298) while in subpopulation SAS AF = 0.00643 (31/4818). AF 95% confidence interval is 0.00466. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.307C>T	p.Arg103Cys	missense_variant	Exon 4 of 27	ENST00000005226.12	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4 link	c.307C>T	p.Arg103Cys	missense_variant	Exon 4 of 21	ENST00000318024.9	NP_005700.2	Q9Y6N9-1A0A0S2Z4U9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 link	c.307C>T	p.Arg103Cys	missense_variant	Exon 4 of 27	5	NM_153676.4	ENSP00000005226.7		Q9Y6N9-5
USH1C	ENST00000318024.9 link	c.307C>T	p.Arg103Cys	missense_variant	Exon 4 of 21	1	NM_005709.4	ENSP00000317018.4		Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00643

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00105

AC:

263

AN:

251126

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000564

AC:

824

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

547

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00785

AC:

677

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000101

AC:

112

AN:

1112012

Other (OTH)

AF:

0.000530

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000210

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00643

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000908

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000997

AC:

121

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Mar 02, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The USH1C c.307C>T; p.Arg103Cys variant (rs397517880) has been reported in the heterozygous state in a single individual diagnosed with Usher Syndrome type I (Besnard 2014). Another variant affecting this codon, Arg103His, has also been reported in two individuals with Usher Syndrome (Roux 2006, Saihan 2011). However, this variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 0.8% (identified on 261 out of 30,776 chromosomes, including 3 homozygotes) and is classified as a variant of uncertain significance in ClinVar (ID: 48013). The arginine at position 103 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Arg103Cys variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on the available information, the clinical significance of the p.Arg103Cys variant cannot be determined with certainty. -

Jul 15, 2019

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32467589, 30245029, 24498627) -

not specified

Uncertain:1

Sep 04, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Arg103Cys v ariant in USH1C has been reported in one French individual with Usher syndrome t ype I (Besnard 2014) and has been identified in one Indian individual with senso rineural hearing loss by our laboratory (LMM unpublished data); however a second variant in USH1C was not detected in either individual. This variant is absent from large population studies. Another amino acid change at this position (Arg10 3His) has been identified in two individuals with Usher syndrome who were compou nd heterozygous with another pathogenic USH1C (Roux 2006, Saihan 2011), and the variant segregated with disease in an affected sibling of one of those individua ls (Saihain 2011). These data suggest that variants that alter the arginine resi due at position 103 may not be tolerated. Computational prediction tools and con servation analyses suggest that the Arg103Cys variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, while there is some suspicion for a pathogenic role, the clinical signifi cance of the Arg103Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

T;.;.;.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.022

T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.2

L;.;L;L;.

PhyloP100

4.8

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.4

D;D;D;D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

D;.;D;.;.

Vest4

0.96

MutPred

0.78

Loss of methylation at R103 (P = 0.0217);.;Loss of methylation at R103 (P = 0.0217);Loss of methylation at R103 (P = 0.0217);.;

MVP

0.62

MPC

0.45

ClinPred

0.17

GERP RS

4.5

Varity_R

0.91

gMVP

0.77

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over