rs541918040

Positions:

• chr1-216217499-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_206933.4(USH2A):​c.3045C>G​(p.His1015Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,613,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1015Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:14
• Conservation: PhyloP100: 1.25

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

USH2A-AS1 (HGNC:):

ACMG classification

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=0.2561918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.3045C>G	p.His1015Gln	missense_variant	15/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.3045C>G	p.His1015Gln	missense_variant	15/21		NP_009054.6
USH2A-AS1	XR_922596.4	n.692-7888G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.3045C>G	p.His1015Gln	missense_variant	15/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.3045C>G	p.His1015Gln	missense_variant	15/21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.3045C>G	p.His1015Gln	missense_variant	15/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000879 AC: 22 AN: 250370 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000136 AC: 199 AN: 1461060 Hom.: 0 Cov.: 33 AF XY: 0.000146 AC XY: 106 AN XY: 726824

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74310

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2021	The p.His1015Gln variant (rs541918040) has been previously observed once in a cohort of non-syndromic retinitis pigmentosa patients (Pierrache 2016); however, no specific clinical or segregation details were proved. It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.009% (identified in 24 out of 276,088 chromosomes). The histidine at codon 1015 is weakly conserved considering 12 species (Alamut software v2.9), and computational analyses return mixed results regarding the effect of this variant on USH2A protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing). Taken together, based on the available information, the clinical significance of the p.His1015Gln variant cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26927203, 31877679) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	USH2A: PM2, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1015 of the USH2A protein (p.His1015Gln). This variant is present in population databases (rs541918040, gnomAD 0.01%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 26927203, 31877679). ClinVar contains an entry for this variant (Variation ID: 179958). 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 USH2A protein function with a negative predictive value of 95%. 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. -

Retinitis pigmentosa 39 Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Usher syndrome type 2A Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 04, 2014	The His1015Gln variant in USH2A has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational pr ediction tools and conservation analyses do not provide strong support for or ag ainst an impact to the protein. In summary, the clinical significance of the His 1015Gln variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 07, 2024	Variant summary: USH2A c.3045C>G (p.His1015Gln) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 250370 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (8.8e-05 vs 0.011), allowing no conclusion about variant significance. c.3045C>G has been reported in the literature as a non-informative genotype (second allele not specified and/or with conflicting interpretations of pathogenicity) in individuals with non-syndromic or sporadic forms of Retinitis Pigmentosa (example, Pierrache_2016, Karali_2019, Molina-Ramirez_2020, Bahena_2022) or as a compound heterozygous genotype with another pathogenic variant in at-least one case with Retinitis Pigmentosa (example, Haer-Wigman_2017). These data do not allow any conclusion about variant significance. At-least one of the cases ascertained above reported this variant as a heterozygous genotype inherited along with a homozygous co-occurring pathogenic variant(s) in the IDUA gene, supporting the diagnosis of MPS 1S or Scheie syndrome, that can have phenotypic overlap with hearing impairment and retinal degeneration (IDUA c.956C>T, p.Ala319Val). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28224992, 26927203, 31877679, 32176120, 30902645, 34148116). ClinVar contains an entry for this variant (Variation ID: 179958). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jun 26, 2017

- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.16
Sift	Benign	0.097	T;T
Sift4G	Uncertain	0.029	D;D
Polyphen		0.91	P;P
Vest4		0.40
MutPred		0.47		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.90
MPC		0.20
ClinPred		0.085	T
GERP RS		1.9
Varity_R		0.091
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs541918040; hg19: chr1-216390841;