VCV000617918.38 - ClinVar

NM_001020658.2(PUM1):c.3439C>T (p.Arg1147Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001020658.2(PUM1):c.3439C>T (p.Arg1147Trp)

Variation ID: 617918 Accession: VCV000617918.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p35.2 1: 30933339 (GRCh38) [ NCBI UCSC ] 1: 31406186 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 5, 2018	Oct 20, 2024	Apr 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001020658.2:c.3439C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001018494.1:p.Arg1147Trp	missense
NM_014676.3:c.3433C>T	NP_055491.1:p.Arg1145Trp	missense
NC_000001.11:g.30933339G>A
NC_000001.10:g.31406186G>A

Protein change

R1145W, R1147W

Other names

Canonical SPDI

NC_000001.11:30933338:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

effect on RNA stability; Variation Ontology [ VariO:0301]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 607204.0002 dbSNP: rs1557539450 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PUM1		-	-	GRCh38 GRCh37	214	237

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 7, 2023	RCV001090921.25
Spinocerebellar ataxia 47	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 24, 2020	RCV000755727.8
Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism	Likely pathogenic (2)	criteria provided, single submitter	Apr 29, 2024	RCV003768266.3
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Jul 30, 2021	RCV002533778.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Apr 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000883224.2 First in ClinVar: Feb 18, 2019 Last updated: May 07, 2024	Publications: PubMed (4) PubMed: 29474920‚ 30903679‚ 31859446‚ 35386260 Comment: This variant is interpreted as Likely Pathogenic, for Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism, autosomal dominant. The following ACMG Tag(s) were applied: … (more) This variant is interpreted as Likely Pathogenic, for Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls or at extremely low frequency if recessive in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2_supporting). Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3 ). Confirmed de novo (PS2) (PMID: 29474920, 30903679, 31859446, 35386260). Prevalence in affected individuals statistically increased over controls (PS4_supporting) . Well-established functional studies show a deleterious effect ( PS3_supporting) (https://www.ncbi.nlm.nih.gov/pubmed/29474920). (less)
Pathogenic (Oct 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246695.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Jun 24, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Spinocerebellar ataxia 47 Affected status: yes Allele origin: de novo	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-SouthSeq Accession: SCV001439354.1 First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020	Comment: ACMG codes:PS2; PS3; PS4M; PM2; PP3 Number of individuals with the variant: 1 Clinical Features: Seizures (present) , Intrauterine growth retardation (present) , Small for gestational age (present) , Abnormality of the face (present) , Abnormality of skin pigmentation (present) … (more) Seizures (present) , Intrauterine growth retardation (present) , Small for gestational age (present) , Abnormality of the face (present) , Abnormality of skin pigmentation (present) , Abnormality of limbs (present) , Cryptorchidism (present) , Limb hypertonia (present) , Polyhydramnios (present) , Anemia (present) (less)
Pathogenic (Sep 07, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001773477.2 First in ClinVar: Aug 07, 2021 Last updated: Sep 14, 2023	Comment: Published functional studies demonstrate a damaging effect (moderately impaired PUM1 repression activity) (Gennarino et al., 2018); Not observed at significant frequency in large population cohorts … (more) Published functional studies demonstrate a damaging effect (moderately impaired PUM1 repression activity) (Gennarino et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29474920, 34930662, 31859446, 30903679, 35386260) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinocerebellar ataxia 47 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV003804165.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 29474920 Age: 0-9 years Sex: male
Likely pathogenic (Jul 30, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003530897.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 29474920‚ 30903679‚ 31859446 Comment: The c.3439C>T (p.R1147W) alteration is located in exon 22 (coding exon 21) of the PUM1 gene. This alteration results from a C to T substitution … (more) The c.3439C>T (p.R1147W) alteration is located in exon 22 (coding exon 21) of the PUM1 gene. This alteration results from a C to T substitution at nucleotide position 3439, causing the arginine (R) at amino acid position 1147 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD), the PUM1 c.3439C>T alteration was not observed, with coverage at this position. This alteration has been described to occur de novo in three unrelated individuals who presented with a neurodevelopmental disorder and similar additional features including epilepsy, dysmorphic facial features, hypotonia, cryptorchidism, strabismus, and various brain anomalies on MRI (Bonnemason-Carrere, 2019; Gennarino, 2018; Voet, 2020). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for the p.R1147W alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Pathogenic (Feb 21, 2024)	no assertion criteria provided Method: literature only	NEURODEVELOPMENTAL DISORDER WITH MOTOR ABNORMALITIES, SEIZURES, AND FACIAL DYSMORPHISM Affected status: not provided Allele origin: germline	OMIM Accession: SCV000747047.3 First in ClinVar: May 05, 2018 Last updated: Mar 10, 2024	Publications: PubMed (4) PubMed: 29474920‚ 30903679‚ 31859446‚ 35386260 Comment on evidence: In a 9-year-old girl (subject 11) with neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism (NEDMSF; 620719), Gennarino et al. (2018) identified a de … (more) In a 9-year-old girl (subject 11) with neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism (NEDMSF; 620719), Gennarino et al. (2018) identified a de novo heterozygous G-to-A transition (chr1.31,406,186G-A, GRCh37) in the PUM1 gene, resulting in an arg1147-to-trp (R1147W) substitution at a highly conserved residue adjacent to the eighth PUM-HD repeat just outside the PUM-HD (RNA-binding) domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Patient cells showed only 43% residual wildtype PUM1 protein levels compared to wildtype, consistent with haploinsufficiency. PUM1 mRNA levels were normal, but mRNA and protein levels of known PUM1 targets, including ATXN1 (601556) and E2F3 (600427), were abnormally increased by 51% and 66%, respectively. In vitro transfection studies in HEK293 cells showed that overexpression of the R1147W variant was able to reduce ATXN1 and E2F3 levels. In a boy with NEDMSF, Bonnemason-Carrere et al. (2019) identified a de novo heterozygous R1147W mutation in the PUM1 gene. The mutation, which was found by trio-based whole-exome sequencing, had previously been identified by Gennarino et al. (2018). The boy was also found to carry a heterozygous variant in the GRIA3 gene (305915), which the authors classified as a variant of unknown significance. In a 15-year-old boy (P1) with NEDMSF, Voet et al. (2020) identified a de novo heterozygous R1147W mutation in the PUM1 gene. The mutation, which was found by whole-exome sequencing, was not present in public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. In a 3-year-old Chinese girl with NEDMSF, Ye et al. (2022) identified a de novo heterozygous R1147W substitution in the PUM1 gene. The mutation, which was found by trio-based whole-exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Spinocerebellar ataxia 47 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Neurology Department, Shenzhen Children's Hospital Accession: SCV001976645.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021	Publications: DOI: 10.1002/ajmg.a.61127 DOI: 10.1002/ajmg.a.61127 DOI: 10.1016/j.cell.2018.02.006 DOI: 10.1016/j.cell.2018.02.006 DOI: 10.1002/ajmg.a.61463 DOI: 10.1002/ajmg.a.61463 Comment: Trio-based WES revealed that the exon 22 of the PUM1 gene had a de novo heterozygous missense variant which is otherwise absent in population databases … (more) Trio-based WES revealed that the exon 22 of the PUM1 gene had a de novo heterozygous missense variant which is otherwise absent in population databases (dbSNP, ExAC, and GnomAD). Thus far, at least three unrelated patients with this variant have been reported (Bonnemason-Carrere et al., 2019; Gennarino et al., 2018; Voet et al., 2020), and all of them were de novo. Upon Western blotting analysis, it was found that the PUM1 protein stability was markedly compromised by this variant (Gennarino et al., 2018). Taken together, according to the American college of medical genetics and genomics guidelines, this variant is considered pathogenic (Richards et al., 2015). (less) Indication for testing: Status epilepticus，Global developmental delay Age: 0-9 years Sex: female Ethnicity/Population group: Asian Geographic origin: China Testing laboratory: AmCare Genomics Lab Date variant was reported to submitter: 2019-11-19 Testing laboratory interpretation: Pathogenic

Comment:

This variant is interpreted as Likely Pathogenic, for Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls or at extremely low frequency if recessive in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2_supporting). Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3 ). Confirmed de novo (PS2) (PMID: 29474920, 30903679, 31859446, 35386260). Prevalence in affected individuals statistically increased over controls (PS4_supporting) . Well-established functional studies show a deleterious effect ( PS3_supporting) (https://www.ncbi.nlm.nih.gov/pubmed/29474920).

Comment:

Published functional studies demonstrate a damaging effect (moderately impaired PUM1 repression activity) (Gennarino et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29474920, 34930662, 31859446, 30903679, 35386260)

Comment:

The c.3439C>T (p.R1147W) alteration is located in exon 22 (coding exon 21) of the PUM1 gene. This alteration results from a C to T substitution at nucleotide position 3439, causing the arginine (R) at amino acid position 1147 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD), the PUM1 c.3439C>T alteration was not observed, with coverage at this position. This alteration has been described to occur de novo in three unrelated individuals who presented with a neurodevelopmental disorder and similar additional features including epilepsy, dysmorphic facial features, hypotonia, cryptorchidism, strabismus, and various brain anomalies on MRI (Bonnemason-Carrere, 2019; Gennarino, 2018; Voet, 2020). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for the p.R1147W alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.

Comment:

Trio-based WES revealed that the exon 22 of the PUM1 gene had a de novo heterozygous missense variant which is otherwise absent in population databases (dbSNP, ExAC, and GnomAD). Thus far, at least three unrelated patients with this variant have been reported (Bonnemason-Carrere et al., 2019; Gennarino et al., 2018; Voet et al., 2020), and all of them were de novo. Upon Western blotting analysis, it was found that the PUM1 protein stability was markedly compromised by this variant (Gennarino et al., 2018). Taken together, according to the American college of medical genetics and genomics guidelines, this variant is considered pathogenic (Richards et al., 2015).

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on RNA stability (VariO:0301)			Neurology Department, Shenzhen Children's Hospital Accession: SCV001976645.1	Publications DOI: 10.1002/ajmg.a.61127 DOI: 10.1016/j.cell.2018.02.006 DOI: 10.1002/ajmg.a.61463

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A de novo PUM1 Variant in a Girl With a Dravet-Like Syndrome: Case Report and Literature Review.	Ye Y	Frontiers in pediatrics	2022	PMID: 35386260
PUM1 haploinsufficiency is associated with syndromic neurodevelopmental delay and epilepsy.	Voet J	American journal of medical genetics. Part A	2020	PMID: 31859446
PADDAS syndrome associated with hair dysplasia caused by a de novo missense variant of PUM1.	Bonnemason-Carrere P	American journal of medical genetics. Part A	2019	PMID: 30903679
A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.	Gennarino VA	Cell	2018	DOI: 10.1016/j.cell.2018.02.006
A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.	Gennarino VA	Cell	2018	PMID: 29474920
-	-	-	-	DOI: 10.1002/ajmg.a.61127
-	-	-	-	DOI: 10.1002/ajmg.a.61463

Text-mined citations for rs1557539450 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001020658.2(PUM1):c.3439C>T (p.Arg1147Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1557539450 ...