ClinVar Miner

Submissions for variant NM_207352.4(CYP4V2):c.992A>C (p.His331Pro) (rs199476197)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000490060 SCV000577474 pathogenic not provided 2018-12-24 criteria provided, single submitter clinical testing The H331P variant in the CYP4V2 gene has been reported previously in association with Bietti crystalline corneoretinal dystrophy (BCD), and is seen in 7.4% of alleles in the Chinese population with BCD (Xiao et al., 2011; Huang et al., 2015; Yin et al., 2016). The H331P variant is observed in 19/17248 (0.11%) alleles from individuals of East Asian background, in large population cohorts (Lek et al., 2016). The H331P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies show H331P has significantly lower steady-state protein expression levels compared to wild type and lipid profiling data are consistent with reduced metabolism of polyunsaturated fatty acids for the H331P variant (Nakano et al., 2012). We interpret H331P as a pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000032552 SCV000731786 pathogenic Bietti crystalline corneoretinal dystrophy 2017-08-01 criteria provided, single submitter clinical testing The p.His331Pro (NM207352.3 c.992A>C) variant in CYP4V2 has been reported in at least 6 homozygous and 14 compound heterozygous individuals with Bietti crystall ine dystrophy and one family with retinitis pigmentosa (Huang 2015, Liu 2015, Yi n 2016, and Jiao 2017). In vitro functional studies on the p.His331Pro variant provide evidence supporting an impact on protein function (Nakano 2012). This va riant has been identified in 0.11% (19/17248) of East Asian chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs19 9476197). Although this variant has been seen in the general population, its fre quency is low enough to be consistent with a recessive carrier frequency. In sum mary, this variant meets criteria to be classified as pathogenic for Bietti crys talline dystrophy in an autosomal recessive manner based upon its biallelic occu rrence in affected individuals and impact in functional studies.
Invitae RCV000490060 SCV001224645 pathogenic not provided 2020-02-08 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 331 of the CYP4V2 protein (p.His331Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is present in population databases (rs199476197, ExAC 0.1%). This variant has been observed in many individuals and families affected with Bietti crystalline corneoretinal dystrophy (PMID: 15042513, 25611614, 26971461, 28848678). ClinVar contains an entry for this variant (Variation ID: 39275). This variant has been reported to affect CYP4V2 protein function (PMID: 22772592). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074450 SCV001240034 pathogenic Retinal dystrophy 2017-05-05 criteria provided, single submitter clinical testing
GeneReviews RCV000032552 SCV000056219 pathologic Bietti crystalline corneoretinal dystrophy 2012-04-12 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000032552 SCV000246148 pathogenic Bietti crystalline corneoretinal dystrophy 2005-06-01 no assertion criteria provided literature only

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