rs149529031

Positions:

chr17-74920526-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_173477.5(USH1G):c.310A>G(p.Met104Val) variant causes a missense change. The variant allele was found at a frequency of 0.000302 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

USH1G
NM_173477.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.02

Variant links:

Genes affected

USH1G (HGNC:16356): (USH1 protein network component sans) This gene encodes a protein that contains three ankyrin domains, a class I PDZ-binding motif and a sterile alpha motif. The encoded protein interacts with harmonin, which is associated with Usher syndrome type 1C. This protein plays a role in the development and maintenance of the auditory and visual systems and functions in the cohesion of hair bundles formed by inner ear sensory cells. Mutations in this gene are associated with Usher syndrome type 1G (USH1G). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

USH1G links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-74920526-T-C is Pathogenic according to our data. Variant chr17-74920526-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166402.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=5}. Variant chr17-74920526-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
USH1G	NM_173477.5 linkuse as main transcript	c.310A>G	p.Met104Val	missense_variant	2/3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	2/3		NP_001269418.1
USH1G	XM_011524296.2 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	2/3		XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1G	ENST00000614341.5 linkuse as main transcript	c.310A>G	p.Met104Val	missense_variant	2/3	1	NM_173477.5	ENSP00000480279	P1
USH1G	ENST00000579243.1 linkuse as main transcript	c.257A>G	p.His86Arg	missense_variant, NMD_transcript_variant	2/3	2		ENSP00000462568

Frequencies

GnomAD3 genomes

AF:

0.000282

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251262

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000304

AC:

444

AN:

1461410

Hom.:

Cov.:

AF XY:

0.000281

AC XY:

204

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000379

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000282

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000276

Hom.:

Bravo

AF:

0.000261

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2024	Identified in trans with a second variant in affected individuals in a family with nonsyndromic hearing loss (PMID: 25255398); In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies are inconclusive, suggesting that the variant may disrupt interactions with some proteins but that sufficient residual function may be retained (PMID: 28137943, 31637240); This variant is associated with the following publications: (PMID: 30245029, 28137943, 31637240, 30828346, 27353947, 37734845, 25255398, 27068579) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 104 of the USH1G protein (p.Met104Val). This variant is present in population databases (rs149529031, gnomAD 0.03%). This missense change has been observed in individual(s) with non-syndromic deafness (PMID: 25255398). ClinVar contains an entry for this variant (Variation ID: 166402). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt USH1G protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects USH1G function (PMID: 31637240). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 29, 2013	The Met104Val variant in USH1G has not been reported in individuals with hearing loss, but has been identified in 3/8600 (0.03%) European American chromosomes b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP r s149529031). Computational analyses (biochemical amino acid properties, conserv ation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or agai nst an impact to the protein. In summary, additional data is needed to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 06, 2024	Variant summary: USH1G c.310A>G (p.Met104Val) results in a conservative amino acid change located in the ANK3 domain (Sorusch_2019) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251262 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH1G causing Usher Syndrome (0.00014 vs 0.0014), allowing no conclusion about variant significance. c.310A>G has been reported in the literature in compound heterozygosity with another variant in the USH1G gene (c.780insGCAC, p.Tyr261Alafs*96) in two Dutch siblings affected with non-syndromic hearing loss (NSHL) (example, Oonk_2015). It has also been reported as a VUS with a non-informative genotype (i.e., second allele not specified) in settings of multigene panel testing in cohorts of patients with NSHL (example, Sommen_2016), as a non-informative genotype in settings of exome sequencing of cohorts with Retinal dystrophies (example, Tiwari_2016), as a non-informative genotype in settings of multigene panel testing of cohorts with sporadic Menieres disease (MD) (example, Gallego-Martinez_2019). The Deafness Variation Database (DVB) cites this variant as pathogenic based on a custom-built internal computational pipeline (example, Azaiez_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of USH1G binding (residual activity at approximately 10-30% of wild-type) to intraflagellar transport (IFT) molecules in the primary cilia (example, Sorusch_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30245029, 27353947, 30828346, 25255398, 27068579, 31637240). ClinVar contains an entry for this variant (Variation ID: 166402). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hearing impairment

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Strong, PM2_Supporting, BP4_Supporting -

USH1G-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 23, 2018

The USH1G c.310A>G (p.Met104Val) variant has been reported in three studies in which it is identified in a total of four individuals. The p.Met104Val variant was reported in a compound heterozygous state with a frameshift variant in two siblings from a non-consanguineous Dutch family with early onset hearing loss, but no eye abnormalities or signs of retinitis pigmentosa (Oonk et al. 2015). The variant was also reported in a homozygous state in one individual with no specific phenotype details from a cohort of patients with prelingual, moderate to profound probable autosomal recessive non-syndromic hearing loss (Sommen et al. 2016), and in a heterozygous state in one individual with a retinal dystrophy phenotype who was also compound heterozygous for two variants in the ABCA4 gene (Tiwari et al. 2016). The variant was absent from 350 Dutch control subjects and is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Molecular modelling predicts that the p.Met104Val variant causes a change at the third ankyrin domain surface but does not alter the domain structure (Oonk et al. 2015). Based on the evidence, the p.Met104Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for USH1G-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.0023

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.031

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.39

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

Sift4G

Benign

1.0

Polyphen

0.081

Vest4

0.93

MVP

0.24

ClinPred

0.071

GERP RS

3.8

Varity_R

0.33

gMVP

0.77

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