rs371626423
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_153676.4(USH1C):c.2192G>A(p.Arg731Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,694 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. R731W) has been classified as Uncertain significance.
Frequency
Consequence
NM_153676.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH1C | NM_153676.4 | c.2192G>A | p.Arg731Gln | missense_variant | 21/27 | ENST00000005226.12 | |
USH1C | NM_005709.4 | c.1292G>A | p.Arg431Gln | missense_variant | 16/21 | ENST00000318024.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH1C | ENST00000005226.12 | c.2192G>A | p.Arg731Gln | missense_variant | 21/27 | 5 | NM_153676.4 | ||
USH1C | ENST00000318024.9 | c.1292G>A | p.Arg431Gln | missense_variant | 16/21 | 1 | NM_005709.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152092Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251048Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135650
GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461484Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34AN XY: 727040
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74424
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 17, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Arg731Gln var iant in USH1C has not been previously reported in individuals with hearing loss, but it has been identified in 7/66508 European chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs371626423). Argin ine (Arg) at position 731 is conserved in mammals but not in evolutionarily dist ant species, with >10 reptiles and fish species having glutamine (Gln) at this p osition, suggesting that this variant may be tolerated. Additional computational prediction tools suggest that this variant may not impact the protein, though t his information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Arg731Gln variant is uncertain, the con servation and computational data suggests that it is more likely to be benign. - |
Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 24, 2017 | - - |
Usher syndrome type 1;C1848604:Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 26, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 15, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 431 of the USH1C protein (p.Arg431Gln). This variant is present in population databases (rs371626423, gnomAD 0.01%). 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: 229602). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at