ClinVar Miner

Submissions for variant NM_004646.3(NPHS1):c.320C>T (p.Ala107Val) (rs386833934)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV000049908 SCV001164378 uncertain significance Finnish congenital nephrotic syndrome 2018-12-03 criteria provided, single submitter research The heterozygous p.Ala107Val variant in NPHS1 was identified by our study in the compound heterozygous state, with a VUS, in one individual with nephrotic syndrome. This variant was seen in 0.006511% (2/30718) of South Asian chromosomes and 0.0009039% (1/110628) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs386833934). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Ala107Val variant in NPHS1 has been reported in two unrelated individuals in the heterozygous state, one with a splice site variant in trans, with nephrotic syndrome (PMID: 20172850). The presence of this variant in combination with a splice site variant and in an individual with nephrotic syndrome increases the likelihood that the p.Ala107Val variant is pathogenic. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3_Supporting (Richards 2015).
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049908 SCV000082317 probable-pathogenic Finnish congenital nephrotic syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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