Submissions for variant NM_001031710.3(KLHL7):c.793+5G>C

gnomAD frequency: 0.00004  dbSNP: rs375718274

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523837	SCV000621643	uncertain significance	not specified	2017-10-18	criteria provided, single submitter	clinical testing	The c.793+5G>C variant in the KLHL7 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant reduces the quality of the splice donor site in intron 6, and is expected to cause abnormal gene splicing. The c.793+5G>C variant is observed in 3/24036 (0.012%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). We interpret c.793+5G>C as a variant of uncertain significance.
Invitae	RCV001057631	SCV001222134	likely pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing	This sequence change falls in intron 6 of the KLHL7 gene. It does not directly change the encoded amino acid sequence of the KLHL7 protein. It affects a nucleotide within the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 452804). This variant has been observed in individual(s) with clinical features of autosomal recessive KLHL7-related conditions (PMID: 35670385; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs375718274, gnomAD 0.01%).
Centre for Human Genetics, University of Kinshasa	RCV002274055	SCV002097242	uncertain significance	PERCHING syndrome	2021-08-11	criteria provided, single submitter	clinical testing	The c.793+5G>C variant in KLHL7, identified here in an African patient from DR Congo, has been previously submitted to ClinVar as a VUS. This variant is present in heterozygous state in 5 individuals in gnomAD (total AF = 0.00003286), including 4 African/African American, and was maternally inherited in this patient. The splice site prediction scores Ada and RF (Jiang et al., 2014) predict that this variant has an effect on splicing. The SpliceAI scores predict that this variant causes the loss of an existing splice donor site. In addition, this individual is also carrying another variant, absent from the mother (the father was not available for testing), the 7:23205323; NM_001031710.2; ENST339077: c.944delG; p.Ser315fs. In summary, the c.793+5G>C is classified as VUS
Mendelics	RCV002248756	SCV002516623	pathogenic	Retinitis pigmentosa 42	2022-05-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV002274055	SCV004801514	uncertain significance	PERCHING syndrome	2021-04-29	criteria provided, single submitter	clinical testing	The KLHL7 c.793+5G>C variant is a splice region variant. A literature search was performed for the gene and cDNA change. No publications were found based on this search. The c.793+5G>C variant is reported at a frequency of 0.000120 in the African/African-American population of the Genome Aggregation Database. The c.793+5G>C variant is predicted to disrupt the splice donor site based on a splicing prediction algorithm (Jaganathan et al. 2019). Based on the limited evidence, the c.793+5G>C variant is classified as a variant of uncertain significance for PERCHING syndrome.