rs149529031

Positions:

• chr17-74920526-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5
• Conservation: PhyloP100: 5.02

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]

ACMG classification

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: {Uncertain_significance=5, Likely_pathogenic=2}. Variant chr17-74920526-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1G	NM_173477.5	c.310A>G	p.Met104Val	missense_variant	2/3	ENST00000614341.5
USH1G	NM_001282489.3	c.1A>G	p.Met1?	start_lost	2/3
USH1G	XM_011524296.2	c.1A>G	p.Met1?	start_lost	2/3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152218 Hom.: 0 Cov.: 32

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: 36 AN: 251262 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135894

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.: 0 Cov.: 41 AF XY: 0.000281 AC XY: 204 AN XY: 727022

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: 43 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74366

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.: 0

Bravo AF: 0.000261

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2023	Identified in trans with a second variant in affected individuals in a family with nonsyndromic hearing loss (Maria Oonk et al., 2015); In silico analysis supports 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 (Sorusch et al., 2017; Sorusch et al., 2019); This variant is associated with the following publications: (PMID: 30245029, 28137943, 31637240, 27353947, 27068579, 25255398) -
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	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
Sift4G	Benign	1.0	T
Polyphen		0.081	B
Vest4		0.93
MVP		0.24
ClinPred		0.071	T
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

Other links and lift over

dbSNP: rs149529031; hg19: chr17-72916621;