ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1588G>A (p.Val530Ile) (rs145191978)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129860 SCV000184677 likely benign Hereditary cancer-predisposing syndrome 2015-09-23 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence
Invitae RCV000205363 SCV000261449 uncertain significance Neurofibromatosis, type 1 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 530 of the NF1 protein (p.Val530Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs145191978, ExAC 0.009%). This variant has been observed in an individual affected with pheochromocytoma, who also carried a pathogenic SDHB variant (PMID: 23407919). ClinVar contains an entry for this variant (Variation ID: 141369). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
GeneDx RCV000489208 SCV000577596 likely benign not provided 2020-09-01 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23407919)
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761180 SCV000891096 uncertain significance Acute monocytic leukemia; Acute monoblastic leukemia 2017-04-21 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000205363 SCV001423441 not provided Neurofibromatosis, type 1 no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 04-29-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000489208 SCV001554354 uncertain significance not provided no assertion criteria provided clinical testing The NF1 p.V530I variant was identified in an individual with pheochromocytoma who was hypertensive but did not exhibit any Neurofibromatosis type 1 symptoms; the patient also had another variant in the SDHB gene which authors reported to be pathogenic (Sjursen_2013_PMID_23407919). The variant was identified in dbSNP (ID: rs145191978) and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae and St. Jude Children's Research Hospital Clinical Genomics Lab, andas likely benign by GeneDx). The variant was identified in control databases in 21 of 282376 chromosomes at a frequency of 0.00007437 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 19 of 128982 chromosomes (freq: 0.000147), Other in 1 of 7214 chromosomes (freq: 0.000139) and African in 1 of 24882 chromosomes (freq: 0.00004), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.V530 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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