ClinVar Genomic variation as it relates to human health

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 33111345). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:33111345). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000497724). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

The identified mutation leads to frameshift in the coding part of RPGR gene. Hence, this substitution alters the amino acid sequence and leads to a premature stop codon at position 323 with the complete loss of rest of the protein sequence leading to truncated protein.

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: 29456477, 26445815, 31299979, 31980526, 34265623, 31850270, 33597575, 36056583)

This sequence change creates a premature translational stop signal (p.Thr323Hisfs*19) in the COL11A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL11A2 are known to be pathogenic (PMID: 10677296, 21204229). This variant is present in population databases (rs748440351, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive COL11A2-related conditions (PMID: 29456477, 31299979). ClinVar contains an entry for this variant (Variation ID: 497724). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

This variant has been previously reported in heterozygous state in a patient with fibrocartilage hyperplasia type II [PMID: 31299979] and also reported in 3 Iranian individuals with hearing loss in homozygous state [PMID: 29456477]. Loss-of-function variants in the COL11A2 gene are known to be pathogenic [PMID: 10677296, 21204229].

ACMG: PVS1, PM2_Supporting, PM3_Strong, PP1_Moderate

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr323HisfsX19 variant in COL11A2 has been previously reported in 3 Iranian individuals with hearing loss who were homozygous for the variant. It should be noted that consanguinity was reported for 1 individual, and was likely present for the remaining 2 (Sloan-Heggen 2015, Vona 2017). It has been reported in ClinVar (Variation ID 497724). This variant has also been reported in 34/281618 of the total chromosomes by gnomAD, with the highest frequency of 0.019% (7/35422) in Latino chromosomes (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 323 and leads to a premature termination codon 19 amino acids downstream. However, this variant is present in an in-frame exon that is only present in 1 transcript of COL11A2. Therefore, the impact to the protein is uncertain. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PVS1_Moderate, PM2_Supporting, PM3_Supporting.