ClinVar Genomic variation as it relates to human health

The c.1074delT deletion in the ANTXR2 gene is one of three frameshift variants in the exon 13 hotspotthat accounts for approximately 60% of all pathogenic alleles (Yan et al., 2013). The c.1074delT variant,denoted as c.1602delT due to alternative nomenclature, was reported in the homozygous state in twosiblings in a consanguineous Kuwaiti family with features consistent with infantile systemic hyalinosis(Hanks et al., 2003). It was also also reported previously in the homozygous state in an individual from aconsanguineous Moroccan family with features consistent with juvenile hyaline fibromatosis (Jaouad et al.,2014). Functional studies indicate the c.1074delT deletion leads to abnormalities in the mRNA and proteinfolding, resulting in degradation (Yan et al., 2013). The c.1074delT variant causes a frameshift startingwith codon Alanine 359, changes this amino acid to a Histidine residue, and creates a premature Stopcodon at position 50 of the new reading frame, denoted p.Ala359HisfsX50. This variant is predicted tocause loss of normal protein function either through protein truncation or nonsense-mediated mRNAdecay. The c.1074delT deletion was not observed in approximately 5,900 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. We interpret c.1074delT as a pathogenic variant.

This frameshifting variant in exon 13 of 16 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a compound heterozygous and as a homozygous change in patients with hyaline fibromatosis syndrome (PMID: 14508707, 21328543). It is found within a hotspot on exon 13 which contains several recurrent frameshift variants that together account for approximately 60% of all pathogenic alleles in ANTXR2 (PMID: 23554269). Functional studies using patient fibroblasts and HeLa cells demonstrated that this variant leads to very low levels of mRNA expression and proteasome-mediated degradation of the mistranslated protein (PMID: 23554269). It is present in the heterozygous state in the gnomAD population database at a frequency of .004% (11/270038) and thus is presumed to be rare. Based on the available evidence, the p.Ala359HisfsTer50 variant is classified as Pathogenic.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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 (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000040, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000419342, PMID:14508707). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

ACMG classification criteria: PVS1 very strong, PS3 supporting, PM2 moderated, PM3 very strong