Submissions for variant NM_144599.5(NIPA1):c.316G>A (p.Gly106Arg)

dbSNP: rs104894490

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002631	SCV000541115	pathogenic	Hereditary spastic paraplegia 6	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 106 of the NIPA1 protein (p.Gly106Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia (HSP) (PMID: 15643603, 15711826, 16267846, 21599812, 22302102, 24075313). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as G341A. ClinVar contains an entry for this variant (Variation ID: 2523). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NIPA1 function (PMID: 17166836, 19091982, 19620182, 20816793, 24128679). For these reasons, this variant has been classified as Pathogenic.
Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	RCV000516051	SCV000574453	pathogenic	Hereditary spastic paraplegia	2017-03-07	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000713477	SCV000705178	pathogenic	not provided	2017-01-12	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000713477	SCV000844089	pathogenic	not provided	2024-06-07	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene. This variant results in the same amino acid change as another variant considered to be pathogenic (c.316G>C). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID 17166836, 19091982, 20816793)
CeGaT Center for Human Genetics Tuebingen	RCV000713477	SCV001248889	pathogenic	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000002631	SCV001367366	pathogenic	Hereditary spastic paraplegia 6	2019-09-03	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS2,PS3,PM2,PM5,PP3,PP5.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000713477	SCV001448094	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000002631	SCV001451132	pathogenic	Hereditary spastic paraplegia 6		criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000002631	SCV002072921	pathogenic	Hereditary spastic paraplegia 6		criteria provided, single submitter	clinical testing	The missense variant p.G106R in NIPA1 (NM_144599.5) has been reported previously in affected patients (Hedera P et al; Morais S et al). The variant has been previously reported as de novo mutation. The variant has been submitted to ClinVar as Pathogenic. The p.G106R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G106R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 106 of NIPA1 is conserved in all mammalian species. The nucleotide c.316 in NIPA1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000516051	SCV002105425	pathogenic	Hereditary spastic paraplegia	2017-01-03	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000713477	SCV002520049	pathogenic	not provided	2021-12-28	criteria provided, single submitter	clinical testing	PP1, PM2, PM6, PS1, PS3, PS4_moderate
OMIM	RCV000002631	SCV000022788	pathogenic	Hereditary spastic paraplegia 6	2005-02-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003981	SCV001162007	pathogenic	Spastic paraplegia		no assertion criteria provided	research
Solve-RD Consortium	RCV000002631	SCV005091460	likely pathogenic	Hereditary spastic paraplegia 6	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team