ClinVar Miner

Submissions for variant NM_000096.4(CP):c.1430C>T (p.Pro477Leu)

gnomAD frequency: 0.00242  dbSNP: rs35331711
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000192950 SCV000247086 uncertain significance not specified 2015-03-13 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000398768 SCV000441637 likely benign Deficiency of ferroxidase 2018-01-12 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae RCV000398768 SCV000636873 benign Deficiency of ferroxidase 2024-01-30 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000398768 SCV001440774 likely benign Deficiency of ferroxidase 2019-01-01 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001355940 SCV001962531 likely benign not provided 2023-11-01 criteria provided, single submitter clinical testing CP: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000192950 SCV004030001 likely benign not specified 2023-07-14 criteria provided, single submitter clinical testing Variant summary: CP c.1430C>T (p.Pro477Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 251416 control chromosomes, predominantly at a frequency of 0.004 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in CP causing Neurodegeneration With Brain Iron Accumulation phenotype (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1430C>T has been reported in the literature in individuals affected with Hyperferritinemia (Corradini_2021). This report does not provide unequivocal conclusions about association of the variant with Neurodegeneration With Brain Iron Accumulation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33774058). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355940 SCV001550970 likely benign not provided no assertion criteria provided clinical testing The CP p.Pro477Leu variant was identified in 1 of 352 proband chromosomes (frequency: 0.003) from individuals or families with Parkinson disease but was also present in 1 of 360 control chromosomes (frequency: 0.003) from healthy individuals (Hochstrasser_2004_PMID:15557511). The variant was identified in dbSNP (ID: rs35331711), LOVD 3.0 and ClinVar (classified as uncertain significance by Illumina and Genetic Services Laboratory, University of Chicago, as likely benign by Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen and as benign by Invitae). The variant was identified in control databases in 680 of 282808 chromosomes (2 homozygous) at a frequency of 0.002404 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 521 of 129134 chromosomes (freq: 0.004035), Ashkenazi Jewish in 35 of 10364 chromosomes (freq: 0.003377), Other in 20 of 7222 chromosomes (freq: 0.002769), Latino in 50 of 35438 chromosomes (freq: 0.001411), European (Finnish) in 34 of 25124 chromosomes (freq: 0.001353), African in 19 of 24964 chromosomes (freq: 0.000761) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the East Asian population. Although the p.Pro477 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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