11-17509546-G-C

Position:

chr11-17509546-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153676.4(USH1C):c.1823C>G(p.Pro608Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000692 in 1,602,700 control chromosomes in the GnomAD database, including 1 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. P608S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00070 ( 1 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:2

Conservation

PhyloP100: 4.44

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18056676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4 linkuse as main transcript	c.1823C>G	p.Pro608Arg	missense_variant	18/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4 linkuse as main transcript	c.1285-7566C>G		intron_variant		ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 linkuse as main transcript	c.1823C>G	p.Pro608Arg	missense_variant	18/27	5	NM_153676.4	ENSP00000005226		Q9Y6N9-5
USH1C	ENST00000318024.9 linkuse as main transcript	c.1285-7566C>G		intron_variant		1	NM_005709.4	ENSP00000317018	P1	Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.000593

AC:

AN:

151748

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000723

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00102

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000486

AC:

117

AN:

240790

Hom.:

AF XY:

0.000444

AC XY:

AN XY:

130508

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000440

Gnomad ASJ exome

AF:

0.000416

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000172

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000818

Gnomad OTH exome

AF:

0.000340

GnomAD4 exome

AF:

0.000702

AC:

1019

AN:

1450952

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

475

AN XY:

720514

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.000473

Gnomad4 ASJ exome

AF:

0.000271

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000118

Gnomad4 FIN exome

AF:

0.0000967

Gnomad4 NFE exome

AF:

0.000850

Gnomad4 OTH exome

AF:

0.000567

GnomAD4 genome

AF:

0.000593

AC:

AN:

151748

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

AN XY:

74062

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000723

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00102

Gnomad4 OTH

AF:

0.000481

Alfa

AF:

0.000718

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000470

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 25, 2018	The p.Pro608Arg variant (rs41282932) has been identified in a homozygous state in a single induvial with non-syndromic hearing loss (Ouyang 2002). However it has been identified in several other cases with an alternate molecular basis for hearing loss, suggesting that it is not a causative variant (Cremers 2007, and Vona 2014). The p.Pro608Arg variant has also been reported to ClinVar (Variation ID: 5148). This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.06 percent (identified on 8 out of 12,984 chromosomes) and is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.05 percent (identified on 124 out of 267,276 chromosomes). The proline at position 608 is weakly conserved (considering 12 species) (Alamut v.2.8.1) and computational analyses of the effects of the p.Pro608Arg variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Pro608Arg variant with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2021	Observed as a heterozygous variant in patients with hearing loss who harbored variants in other hearing loss-related genes (Cremers FP et al., 2007; Vona B et al., 2014; Nonose RW et al., 2018; Roman-Naranjo P et al., 2021); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 16963483, 12136232, 34391192, 30245029, 29739340, 24875298) -

Usher syndrome type 1C

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 08, 2021	NM_005709.3(USH1C):c.1285-7566C>G is an intronic variant classified as a variant of uncertain significance in the context of USH1C-related disorders. c.1285-7566C>G has been observed in cases with relevant disease (PMID: 12136232, 29739340, 16963483, 24875298). Functional assessments of this variant are not available in the literature. c.1285-7566C>G has been observed in population frequency databases (gnomAD: NFE 0.08%). In summary, there is insufficient evidence to classify NM_005709.3(USH1C):c.1285-7566C>G as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 11, 2020	- -

Autosomal recessive nonsyndromic hearing loss 18A

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2002

- -

Meniere disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Jun 21, 2021

Digenic inheritance along with NM_000260.4:c.6247G>A(MYO7A) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 06, 2015

p.Pro608Arg in exon 18 of USH1C: This variant has been previously reported in 3 individuals with Usher syndrome or hearing loss and 2 individuals by our laborat ory; 3 of whom have another genetic etiology to explain their hearing loss (Crem ers 2007, Vera 2014, LMM unpublished data). This variant has also been identifie d in 0.1% (51/60306) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41282932). In summary, the prese nce of this variant in 3 individuals with another etiology for hearing loss and its frequency in the general population suggest that it is likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.93

MutationTaster

Benign

0.98

A;A;A;A

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.8

REVEL

Benign

0.20

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Vest4

0.53

MVP

0.60

MPC

0.31

ClinPred

0.12

GERP RS

5.8

gMVP

0.35

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over