NM_153700.2:c.5188C>T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_153700.2(STRC):c.5188C>T(p.Arg1730*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000548 in 1,605,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_153700.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000272 AC: 4AN: 147210Hom.: 0 Cov.: 21
GnomAD3 exomes AF: 0.0000246 AC: 6AN: 243586Hom.: 0 AF XY: 0.0000228 AC XY: 3AN XY: 131854
GnomAD4 exome AF: 0.0000576 AC: 84AN: 1458254Hom.: 0 Cov.: 32 AF XY: 0.0000676 AC XY: 49AN XY: 725280
GnomAD4 genome AF: 0.0000272 AC: 4AN: 147210Hom.: 0 Cov.: 21 AF XY: 0.0000140 AC XY: 1AN XY: 71512
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 16 Pathogenic:2
PM2_Supporting+PVS1+PM3_Supporting -
This variant occurred in compound heterozygosity with an STRC full gene deletion in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient's family has no other history of hearing loss. This variant is a nonsense leading to an early stop at position 1730 of 1775 in the stereocilin protein. As of January 2023, this variant has been reported to ClinVar as likely pathogenic and is found in 6 heterozygotes on gnomAD. Based on the prediction that this variant leads to a truncated protein, compound heterozygosity with a loss-of-function variant, and goodness of fit of genotype to phenotype, we conclude that this variant is pathogenic. -
not provided Pathogenic:1
Nonsense variant predicted to result in protein truncation as the last 46 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 29339441, 35022556) -
Rare genetic deafness Pathogenic:1
The p.Arg1730X variant in STRC has now been identified by our laboratory in two individuals with hearing loss, who both harbored a deletion of the STRC gene on the remaining allele. This variant has also been identified in 1/5598 Latino chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs139956283); however, this frequency is low enough to be consistent w ith a recessive carrier frequency. This alteration occurs 51 bases from the end of the second to last exon and is predicted to lead to a truncated or absent pro tein. In summary, although additional studies are required to fully establish it s clinical significance, the p.Arg1730X variant is likely pathogenic based on it s identification in multiple affected individuals, its occurrence in trans with another pathogenic variant in the same gene, and the predicted impact to the pro tein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at