ClinVar Genomic variation as it relates to human health

Variant summary: The variant of interest causes a nonsense mutation in exon 8 rresulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. This variant is found in 43/124454 control chromosomes at a frequency of 0.0003455, which does not exceed the maximal expected frequency of a pathogenic allele (0.0031623). The variant of interest has predominantly been observed in Ashkenazi jewish affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.

The Arg245X variant leads to a premature stop codon at position 245, which is pr edicted to lead to a truncated or absent protein. The variant is known to be pat hogenic and is a common cause of Usher syndrome in the Ashkenazi Jewish populati on (Ben-Yosef 2003, Brownstein 2004).

NM_033056.3(PCDH15):c.733C>T(R245*) is classified as pathogenic in the context of PCDH15-related disorders. Sources cited for classification include the following: PMID 15028842, 12711741. Classification of NM_033056.3(PCDH15):c.733C>T(R245*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Nonsense 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: 20301442, 12711741, 15028842, 25525159, 25262649, 27460420, 29490346, 22815625, 30337596, 31456290)

The p.Arg245Ter variant in PCDH15 has been reported in at least 10 individuals with Usher syndrome type 1F (PMID: 12711741, 29490346, 34416374), segregated with disease in 4 affected relatives from 2 families (PMID: 12711741), and has been identified in 0.4% (45/10358) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs111033260). This variant is a known founder in the Ashkenazi Jewish population, and although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 4933) and has been interpreted as pathogenic by multiple submitters. Of the many affected individuals, at least 2 of those were homozygotes, which increases the likelihood that the p.Arg245Ter variant is pathogenic (VariationID: 1185088; PMID: 12711741, 34416374). This nonsense variant leads to a premature termination codon at position 245, which is predicted to lead to a truncated or absent protein. Loss of function of the PCDH15 gene is an established disease mechanism in autosomal recessive Usher syndrome type 1F. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM3, PP1_strong (Richards 2015).

This sequence change creates a premature translational stop signal (p.Arg245*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant is present in population databases (rs111033260, gnomAD 0.4%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 12711741, 22815625, 27460420). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 12711741, 22815625, 27460420). ClinVar contains an entry for this variant (Variation ID: 4933). For these reasons, this variant has been classified as Pathogenic.

PCDH15: PVS1, PM2

Congenital, severe HL; observed together in digenic inheritance with NM_000260.3:c.620A>G

Recessive, congenital, profound HL; USH1F

The PCDH15 c.733C>T variant is predicted to result in premature protein termination (p.Arg245*). This variant has been reported to be causative for Usher syndrome and is one of the most common causative variants in PCDH15 in the Ashkenazi Jewish population with a frequency of 0.43% (Ben-Yosef et al. 2003. PubMed ID: 12711741; Perreault-Micale et al. 2014. PubMed ID: 25307757; Khalaileh et al. 2018. PubMed ID: 29490346; Table S2, Sharon et al. 2019. PubMed ID: 31456290). Nonsense variants in PCDH15 are expected to be pathogenic. This variant is interpreted as pathogenic.

The PCDH15 p.Arg250* variant is known to cause autosomal recessive type 1 Usher syndrome, especially in the Ashkenazi Jewish population (Perreault-Micale_2014_PMID:25307757; Ben-Yosef_2003_PMID:12711741; Brownstein_2004_PMID:15028842). The variant was identified in dbSNP (ID: rs111033260), Cosmic, LOVD 3.0 and in ClinVar (classified as pathogenic by GeneD, Counsyl, Integrated Genetics, Children's Hospital of Philadelphia Division of Human Genetics and Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine for Usher syndrome types 1G, 1, 1D, 1F). The variant was also identified in control databases in 57 of 282438 chromosomes at a frequency of 0.000202 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 45 of 10358 chromosomes (freq: 0.004344), Latino in 8 of 35398 chromosomes (freq: 0.000226), Other in 1 of 7218 chromosomes (freq: 0.000139) and European (non-Finnish) in 3 of 128826 chromosomes (freq: 0.000023); it was not observed in the African, East Asian, European (Finnish) and South Asian populations. The c.748C>T variant leads to a premature stop codon at position 240, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PCDH15 gene are an established mechanism of disease in Usher syndrome and, when found in the homozygous or compound heterozygous state with another pathogenic variant, is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.