chr11-17531233-C-A

Variant names:

• chr11-17531233-C-A
• rs397514500
• NM_153676.4:c.308G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_153676.4(USH1C):​c.308G>T​(p.Arg103Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.19
• Publications: 8 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_153676.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17531233-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.308G>T	p.Arg103Leu	missense_variant	Exon 4 of 27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.308G>T	p.Arg103Leu	missense_variant	Exon 4 of 21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.308G>T	p.Arg103Leu	missense_variant	Exon 4 of 27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.308G>T	p.Arg103Leu	missense_variant	Exon 4 of 21	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251178 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.89	L;.;L;L;.
PhyloP100		7.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.5	D;D;D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;.;D;.;.
Vest4		0.92
MutPred		0.75		Loss of methylation at R103 (P = 0.0217);.;Loss of methylation at R103 (P = 0.0217);Loss of methylation at R103 (P = 0.0217);.;
MVP		0.66
MPC		0.43
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.79
Mutation Taster		=7/93	disease causing

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

Other links and lift over

dbSNP: rs397514500; hg19: chr11-17552780; COSMIC: COSV50014154;