ClinVar Miner

Submissions for variant NM_015443.4(KANSL1):c.2110T>C (p.Ser704Pro)

gnomAD frequency: 0.00015  dbSNP: rs202231419
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001704996 SCV000241325 likely benign not provided 2019-05-17 criteria provided, single submitter clinical testing
Invitae RCV001063848 SCV001228711 benign Koolen-de Vries syndrome 2022-09-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002514008 SCV003719766 uncertain significance Inborn genetic diseases 2022-12-19 criteria provided, single submitter clinical testing The c.2110T>C (p.S704P) alteration is located in exon 8 (coding exon 7) of the KANSL1 gene. This alteration results from a T to C substitution at nucleotide position 2110, causing the serine (S) at amino acid position 704 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000187728 SCV001554426 benign not specified no assertion criteria provided clinical testing The KANSL1 p.Ser704Pro variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs202231419) and ClinVar (classified as likely benign by GeneDx). The variant was identified in control databases in 20 of 282896 chromosomes at a frequency of 0.0000707 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 1 of 7226 chromosomes (freq: 0.000138), African in 3 of 24968 chromosomes (freq: 0.00012), European (non-Finnish) in 15 of 129198 chromosomes (freq: 0.000116) and Latino in 1 of 35440 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. This frequency in control populations is inconsistent with what is expected for the rare, early-onset Koolen-de Vries syndrome caused by pathogenic KANSL1 variants. The p.Ser704 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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