ClinVar Genomic variation as it relates to human health

Variant summary: C9orf75 c.225_235del11 (p.Gly76AlafsX150) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00014 in 35206 control chromosomes (gnomAD). c.225_235del11 (also known as c.42_52del11) has been reported in the literature in multiple individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss 79 (e.g. Rehman_2010, Li_2010, Bashir_2013). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Gly76Alafs*150) in the TPRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPRN are known to be pathogenic (PMID: 20170898, 20170899). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 20170898, 20170899, 23340767). It has also been observed to segregate with disease in related individuals. This variant is also known as c.42_52del. ClinVar contains an entry for this variant (Variation ID: 137). For these reasons, this variant has been classified as Pathogenic.

The p.Gly76AlafsX150 variant in TPRN has been reported in altogether at least 7 individuals from a large consanguineous family with hearing loss from Morocco as well as in 6 affected members of 2 consanguineous families from Pakistan (Bashir 2013 PMID: 23340767, Rehman 2010 PMID: 20170899, Li 2010 PMID: 20170898, Hou 2020 PMID: 31980526) and in ClinVar (Variation ID 137). It has been identified in several subpopulations in gnomAD, including South Asian and European (2/4766 and 17/65678 chromosomes, respectively) (https://gnomad.broadinstitute.org/). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 76 and leads to a premature termination codon 150 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TPRN gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PP1_Strong .

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20170898, 31980526, 23340767, 20170899)

The frameshift c.225_235del(p.Gly76AlafsTer150) variant in TPRN gene has been observed in individual(s) with autosomal recessive nonsyndromic deafness (Bashir et. al., 2013; Rehman et. al., 2010). It has also been observed to segregate with disease in related individuals. This variant is also known as c.42_52del. The p.Gly76AlafsTer150 variant is novel (not in any individuals) in 1000 Genomes. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Glycine 76, changes this amino acid to Alanine residue, and creates a premature Stop codon at position 150 of the new reading frame, denoted p.Gly76AlafsTer150. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPRN are known to be pathogenic (Rehman et. al., 2010). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in TPRN gene, the molecular diagnosis is not confirmed.

The TPRN c.225_235del11 variant is predicted to result in a frameshift and premature protein termination (p.Gly76Alafs*150). This variant was reported in the homozygous state in multiple individuals with hearing loss from two unrelated families (described as c.42_52del11; Li et al. 2010. PubMed ID: 20170898; Bashir et al. 2013. PubMed ID: 23340767). This variant is reported in 0.085% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Frameshift variants in TPRN are expected to be pathogenic. This variant is interpreted as pathogenic.