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White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: POLR3K.
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram changed review comment from: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control.

PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.

This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control.

PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype (onset was in late childhood/ adolescence). This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.

This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram changed review comment from: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp), with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control.

PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.

This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control.

PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.

This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram Tag watchlist was removed from gene: POLR3K.
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram Classified gene: POLR3K as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases (counting the two cases with potential founder variant as one) reported with three different variants in POLR3K (two cases homozygous for the suggested founder missense variant and one case compound heterozygous for a different missense variant and a ~17.8 kb deletion). There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update.
White matter disorders and cerebral calcification - childhood onset v8.10 POLR3K Achchuthan Shanmugasundram Gene: polr3k has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v8.9 POLR3K Achchuthan Shanmugasundram Phenotypes for gene: POLR3K were changed from Leukodystrophy, hypomyelinating, 21, OMIM:619310 to Leukodystrophy, hypomyelinating, 21, OMIM:619310; leukodystrophy, hypomyelinating, 21, MONDO:0030263
White matter disorders and cerebral calcification - childhood onset v8.8 POLR3K Achchuthan Shanmugasundram Publications for gene: POLR3K were set to 30584594; 33659930
White matter disorders and cerebral calcification - childhood onset v8.7 POLR3K Achchuthan Shanmugasundram changed review comment from: PMID:40225923 (2024) reported a single female patient compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp), with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control.

PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.

This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).
White matter disorders and cerebral calcification - childhood onset v8.7 POLR3K Achchuthan Shanmugasundram edited their review of gene: POLR3K: Changed publications to: 30584594, 40225923
White matter disorders and cerebral calcification - childhood onset v8.7 POLR3K Achchuthan Shanmugasundram reviewed gene: POLR3K: Rating: GREEN; Mode of pathogenicity: None; Publications: 40225923; Phenotypes: Leukodystrophy, hypomyelinating, 21, OMIM:619310, leukodystrophy, hypomyelinating, 21, MONDO:0030263; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.98 POLR3K Ivone Leong Tag watchlist tag was added to gene: POLR3K.
Tag founder-effect tag was added to gene: POLR3K.
White matter disorders and cerebral calcification - childhood onset v1.98 POLR3K Ivone Leong Classified gene: POLR3K as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.98 POLR3K Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype.

PMID: 30584594. 2 affected individuals from 2 consanguineous families from same area in Algeria. Affected indviduals had global developmental delay with loss of motor, speech and cognitive milestones. Individuals also showed signs of nystagmus, ataxia, dystonia and spasticity. Both individuals had feeding difficulties and were tube fed, growth failure and microcephaly (-3 SD), and cryptorchidism. 1 patient had optic atrophy and hypodontia and the other patient had hypogonadotropic hypogonadism. Both individuals have the same variant (may be founder effect).

As other members of the same gene family are linked to similar phenotypes this gene has been given an Amber rating.
White matter disorders and cerebral calcification - childhood onset v1.98 POLR3K Ivone Leong Gene: polr3k has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.97 POLR3K Ivone Leong Phenotypes for gene: POLR3K were changed from Hypomyelinating leukodystrophy-21, MIM#619310 to Leukodystrophy, hypomyelinating, 21, OMIM:619310
White matter disorders and cerebral calcification - childhood onset v1.72 POLR3K Zornitza Stark gene: POLR3K was added
gene: POLR3K was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Hypomyelinating leukodystrophy-21, MIM#619310
Review for gene: POLR3K was set to AMBER
Added comment: Two individuals from same ethnic background reported with a common homozygous missense variant in this gene, suggestive of founder effect. Some functional evidence, and note other gene family members are linked to similar phenotypes.

Neurodegenerative phenotype: global developmental delay apparent from infancy with loss of motor, speech, and cognitive milestones in the first decades of life.
Sources: Literature