11-17531402-G-C

Variant names:

• chr11-17531402-G-C
• rs769021971
• NM_153676.4:c.245C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_153676.4(USH1C):​c.245C>G​(p.Ser82Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,520 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S82P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 9.07
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_153676.4	MANE Select	c.245C>G	p.Ser82Cys	missense	Exon 3 of 27	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.245C>G	p.Ser82Cys	missense	Exon 3 of 21	NP_005700.2
	USH1C	NM_001440679.1		c.278C>G	p.Ser93Cys	missense	Exon 3 of 22	NP_001427608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.245C>G	p.Ser82Cys	missense	Exon 3 of 27	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.245C>G	p.Ser82Cys	missense	Exon 3 of 21	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.245C>G	p.Ser82Cys	missense	Exon 3 of 20	ENSP00000436934.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461520 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727018

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111830

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser82Cys variant in USH1C has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Ser82Cys variant is uncer tain.

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

Nov 26, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Usher syndrome type 1C Uncertain:1

Dec 30, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		9.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.40		Loss of phosphorylation at S82 (P = 0.005)
MVP		0.58
MPC		0.38
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.47
gMVP		0.70
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs769021971; hg19: chr11-17552949;