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

dbSNP: rs1557539450

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000755727	SCV000883224	likely pathogenic	Spinocerebellar ataxia 47	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Likely Pathogenic, for Spinocerebellar ataxia 47, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/29474920). PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/29474920).
CeGaT Center for Human Genetics Tuebingen	RCV001090921	SCV001246695	pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000755727	SCV001439354	pathogenic	Spinocerebellar ataxia 47	2020-06-24	criteria provided, single submitter	research	ACMG codes:PS2; PS3; PS4M; PM2; PP3
GeneDx	RCV001090921	SCV001773477	pathogenic	not provided	2023-09-07	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV002533778	SCV003530897	likely pathogenic	Inborn genetic diseases	2021-07-30	criteria provided, single submitter	clinical testing	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.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000755727	SCV003804165	pathogenic	Spinocerebellar ataxia 47		criteria provided, single submitter	clinical testing
OMIM	RCV003768266	SCV000747047	pathogenic	Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism	2024-02-21	no assertion criteria provided	literature only
Neurology Department, Shenzhen Children's Hospital	RCV000755727	SCV001976645	pathogenic	Spinocerebellar ataxia 47		no assertion criteria provided	clinical testing	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).