rs876658109

Positions:

• chr11-17522790-T-G

Variant summary

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

The ENST00000318024.9(USH1C):​c.1013A>C​(p.Glu338Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH1C ENST00000318024.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4	c.1013A>C	p.Glu338Ala	missense_variant	12/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1013A>C	p.Glu338Ala	missense_variant	12/21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.1013A>C	p.Glu338Ala	missense_variant	12/27	5	NM_153676.4	ENSP00000005226
USH1C	ENST00000318024.9	c.1013A>C	p.Glu338Ala	missense_variant	12/21	1	NM_005709.4	ENSP00000317018	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 02, 2016

The p.Glu338Ala variant in USH1C has not been previously reported in individuals with hearing loss or Usher syndrome or in large population studies. Computation al prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of th e p.Glu338Ala variant is uncertain. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2024

The c.1013A>C (p.E338A) alteration is located in exon 12 (coding exon 12) of the USH1C gene. This alteration results from a A to C substitution at nucleotide position 1013, causing the glutamic acid (E) at amino acid position 338 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 17, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 338 of the USH1C protein (p.Glu338Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with USH1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 229598). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Usher syndrome type 1C Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.6	L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.048	D;T;D;T
Polyphen		0.95	P;.;D;.
Vest4		0.72
MutPred		0.21		Gain of MoRF binding (P = 0.0463);.;.;Gain of MoRF binding (P = 0.0463);
MVP		0.80
MPC		0.34
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.53
gMVP		0.49

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: rs876658109; hg19: chr11-17544337;