Submissions for variant NM_001384140.1(PCDH15):c.841A>G (p.Thr281Ala)

gnomAD frequency: 0.00001  dbSNP: rs773843633

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844739	SCV002104028	uncertain significance	not specified	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.841A>G (p.Thr281Ala) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251280 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.841A>G has been reported in the literature in individuals affected with autism spectrum disorders and retinitis pigmentosa (Ishizuka_2016, Liu_2020). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27058588, 33090715). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002545252	SCV003761085	uncertain significance	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The p.Thr281Ala variant in PCDH15 has been reported in 1 individual with Usher syndrome type 1F (PMID: 33090715) and has been identified in 0.02% (3/18384) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs773843633). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 1343722) and has been interpreted as a variant of uncertain significance by Women's Health and Genetics/Laboratory Corporation of America (LabCorp). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Thr281Ala variant is uncertain. ACMG/AMP Criteria applied: BP4 (Richards 2015).