ClinVar Miner

Submissions for variant NM_003906.5(MCM3AP):c.3814G>A (p.Val1272Met)

gnomAD frequency: 0.00037  dbSNP: rs779248881
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000681515 SCV001520502 likely pathogenic Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development 2020-06-09 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Institute of Human Genetics, University of Leipzig Medical Center RCV000681515 SCV002044301 pathogenic Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development 2021-11-25 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PM3_VSTR, PP1_STR
Invitae RCV001861897 SCV002185501 uncertain significance not provided 2022-06-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1272 of the MCM3AP protein (p.Val1272Met). This variant is present in population databases (rs779248881, gnomAD 0.3%). This missense change has been observed in individual(s) with MCM3AP-related conditions (PMID: 28633435, 32202298). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 562048). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change alters MCM3AP gene expression (PMID: 28633435, 32202298). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002307589 SCV002600305 uncertain significance not specified 2022-10-05 criteria provided, single submitter clinical testing Variant summary: MCM3AP c.3814G>A (p.Val1272Met) results in a conservative amino acid change located in the germinal-centre associated nuclear protein, MCM3AP domain (IPR031907) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 240314 control chromosomes, predominantly within the Finnish population of the gnomAD database at a frequency of 0.0025. The variant, c.3814G>A, has been reported in the literature as a compound heterozygous genotype in three siblings with peripheral neuropathy from a Finnish family where it segregated with the disease phenotype and was also reported in an Estonian family in two siblings affected with polyneuropathy and progressive encephalopathy (e.g. Ylikallio_2017, Woldegebrie_2020). Experimental studies using fibroblasts derived from individuals from each of these two families suggest that the variant may reduce mRNA and protein expression, however since the variant of interest was assessed together with the other variants present in these patients, the impact ascribed to this particular variant is difficult to determine (e.g. Ylikallio_2017, Woldegebrie_2020). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Three classified the variant as either pathogenic (n=2) or likely pathogenic (n=1), and two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
OMIM RCV000681515 SCV000808966 pathogenic Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development 2018-09-21 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV000681515 SCV001445985 uncertain significance Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development 2020-11-16 no assertion criteria provided curation The heterozygous p.Val1272Met variant in MCM3AP was identified by our study in the compound heterozygous state, along with another variant of unknown significance, in 2 siblings with peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (PMID: 32202298). The variant has also been reported in 3 Finnish individuals with peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (PMID: 28633435), segregated with disease in 3 affected relatives from 2 families (PMID: 28633435, 32202298), and has been identified in 0.25% (60/24060) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs779248881). This variant has been seen in the general population, in a heterozygous state, at greater rate than expected for disorder. This variant has also been reported in ClinVar (Variation ID: 562048) as pathogenic by OMIM. In vitro functional studies provide some evidence that the variant may slightly impact protein function (PMID: 28633435, 32202298). However, these types of assays may not accurately represent biological function. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein. In summary, the clinical significance of the variant is uncertain. ACMG/AMP Criteria applied: PP1_moderate, BP4, PS3_moderate, BS1 (Richards 2015).

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