ClinVar

Description

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu1640Phe variant in STRC has been previously reported in 9 individuals with hearing loss, 7 of whom were compound heterozygous for a second pathogenic STRC variant (Mandelker 2014, Vona 2016, LMM unpublished data). One individual was homozygous for this variant, but a different nonsense variant was also identified in the homozygous state in this individual, indicating that the variants were in cis (LMM unpublished data). This variant has also been identified in 0.2% (256/128964) of European chromosomes (including 5 homozygotes) by the Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org/; dbSNP rs2860666 and rs2920791). Please note that the Genome Aggregation Database has listed this variant as two separate single nucleotide variants (see rs2860666 and rs2920791) but it was confirmed that the variants occur on the same allele in individuals reported in this database, which is consistent with the variant and amino acid change reported here. Computational prediction tools and conservation analysis suggest that the p.Leu1640Phe variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain due to its relative high frequency in the general population database, including 5 individuals who were homozygous. ACMG/AMP Criteria applied: BS1_Supporting, PM3, BP2.