Submissions for variant NM_018451.5(CPAP):c.659C>T (p.Ser220Leu)

gnomAD frequency: 0.00008  dbSNP: rs201219786

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000287372	SCV000383529	uncertain significance	Microcephaly 6, primary, autosomal recessive	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000340077	SCV000383530	uncertain significance	Seckel syndrome 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850644	SCV002222113	uncertain significance	not provided	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 220 of the CENPJ protein (p.Ser220Leu). This variant is present in population databases (rs201219786, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CENPJ-related conditions. ClinVar contains an entry for this variant (Variation ID: 311628). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002480123	SCV002787756	uncertain significance	Microcephaly 6, primary, autosomal recessive; Seckel syndrome 4	2021-12-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021567	SCV004924058	uncertain significance	Inborn genetic diseases	2022-10-25	criteria provided, single submitter	clinical testing	The c.659C>T (p.S220L) alteration is located in exon 4 (coding exon 3) of the CENPJ gene. This alteration results from a C to T substitution at nucleotide position 659, causing the serine (S) at amino acid position 220 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004537767	SCV004716423	uncertain significance	CENPJ-related disorder	2023-12-14	no assertion criteria provided	clinical testing	The CENPJ c.659C>T variant is predicted to result in the amino acid substitution p.Ser220Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-25484134-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Center for Computational Biology & Bioinformatics, University of California, San Diego	RCV004567855	SCV005050022	uncertain significance	Meniere disease	2024-06-03	no assertion criteria provided	research