rs151045328
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_153676.4(USH1C):c.216G>A(p.Val72Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_153676.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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USH1C | NM_153676.4 | c.216G>A | p.Val72Val | synonymous_variant | Exon 3 of 27 | ENST00000005226.12 | NP_710142.1 | |
USH1C | NM_005709.4 | c.216G>A | p.Val72Val | synonymous_variant | Exon 3 of 21 | ENST00000318024.9 | NP_005700.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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USH1C | ENST00000005226.12 | c.216G>A | p.Val72Val | synonymous_variant | Exon 3 of 27 | 5 | NM_153676.4 | ENSP00000005226.7 | ||
USH1C | ENST00000318024.9 | c.216G>A | p.Val72Val | synonymous_variant | Exon 3 of 21 | 1 | NM_005709.4 | ENSP00000317018.4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251060Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135716
GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461776Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727174
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74348
ClinVar
Submissions by phenotype
not provided Pathogenic:6
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cDNA analysis demonstrated that the c.216 G>A variant creates a new splice site and results in an out-of-frame deletion of 35 nucleotides (Bitner Glindzicz et al., 2000; Lentz et al., 2005); This variant is associated with the following publications: (PMID: 23380860, 12630964, 17407589, 11139240, 21228398, 28041643, 10973248, 15578223, 21436283, 11810303, 29276601, 32581362, 33089500) -
This sequence change affects codon 72 of the USH1C mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the USH1C protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs151045328, gnomAD 0.008%). This variant has been observed in individuals with Usher syndrome 1C (PMID: 11810303, 15578223, 15660226, 17407589). It is commonly reported in individuals of Acadian ancestry (PMID: 17407589, 18665195). ClinVar contains an entry for this variant (Variation ID: 5143). Studies have shown that this variant results in introduction of a cryptic splice site and introduces a premature termination codon (PMID: 10973248, 15578223). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Usher syndrome type 1C Pathogenic:3Other:1
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Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0209 - Splice variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with uncertain effect on protein structure (exon 3 of 27) (PMID: PMID: 10973248, 15578223, 20613545). (P) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant is known as the Acadian allele which causes the most severe form of Usher syndrome type 1 (ClinVar, Deafness Variation Database, PMID: 29276601). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
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Autosomal recessive nonsyndromic hearing loss 18A Pathogenic:2
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Usher syndrome Pathogenic:2
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Variant summary: USH1C c.216G>A alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic exonic 5' splice donor site located two base bairs proximal to this variant. At least one publication reports experimental evidence that this variant affects mRNA splicing due to the creation of a new splice site within exon 3 two base pairs proximal to the site of this variant (Bitner-Glindzicz_2000). The variant allele was found at a frequency of 3.6e-05 in 251060 control chromosomes. c.216G>A has been reported in the literature as a founder mutation of Acadian origin in homozygous and compound heterozygous genotypes among individuals affected with Usher Syndrome (example, Quyang_2003, Bukakowska_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence from a knock in mouse model that demonstrated early onset dual impairment of vision and hearing (Lentz_2010). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Usher syndrome type 1;C1848604:Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Pathogenic:1
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USH1C-related disorder Pathogenic:1
The USH1C c.216G>A is a noncoding alteration. This variant is, however, predicted to strengthen a cryptic donor splice site (Alamut Visual Plus v1.6.1). This variant has been reported in the homozygous or compound heterozygous state in individuals with Usher syndrome and has been described as a founder variant in the Acadian population (Bitner-Glindzicz et al. 2000. PubMed ID: 10973248; Roux et al. 2011. PubMed ID: 21436283; Ebermann et al. 2007. PubMed ID: 17407589; Wafa et al. 2020. PubMed ID: 33089500). A functional study using RT-PCR found that this variant produces a shortened transcript, confirming the splicing prediction algorithms (Bitner-Glindzicz et al. 2000. PubMed ID: 10973248). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Rare genetic deafness Pathogenic:1
The c.216G>A variant in USH1C has been reported in the homozygous or compound he terozygous state in at least 70 individuals with Usher syndrome (Roux 2011, Bitn er-Glindzicz 2000, DeAngelis 2001, Ebermann 2007, Lentz 2007, Lentz 2005, Lentz 2010, Ouyang 2003, Savas 2002, Zwaenepoel 2001). The variant has been shown to c reate a cryptic splice site and produce a 35-bp deletion in the RNA transcript i n lymphoblasts. This 35-bp deletion leads to a frameshift and premature terminat ion codon 189 bases downstream. In summary, this variant meets criteria to be cl assified as pathogenic for autosomal recessive Usher syndrome. -
Usher syndrome type 1 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at