Submissions for variant NM_031448.6(C19orf12):c.391A>G (p.Lys131Glu)

gnomAD frequency: 0.00094  dbSNP: rs146170087

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083182	SCV000647094	benign	Hereditary spastic paraplegia 43	2024-01-22	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714889	SCV000845636	uncertain significance	Hereditary spastic paraplegia 5A	2018-08-07	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000024154	SCV000845637	uncertain significance	Neurodegeneration with brain iron accumulation 4	2018-08-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000024154	SCV001141042	uncertain significance	Neurodegeneration with brain iron accumulation 4	2021-12-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000553096	SCV001151760	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	C19orf12: PM3, PM2:Supporting, BP4, BS2
Institute of Human Genetics, University of Leipzig Medical Center	RCV001083182	SCV001440130	likely benign	Hereditary spastic paraplegia 43	2019-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000553096	SCV001803233	likely benign	not provided	2021-01-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30088953, 21981780, 25592411)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844017	SCV002103566	benign	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: C19orf12 c.391A>G (p.Lys131Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 250744 control chromosomes, predominantly at a frequency of 0.0096 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in C19orf12 causing Neurodegeneration With Brain Iron Accumulation phenotype (0.0006), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: benign (n=1), likely benign (n=3), uncertain significance (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847623	SCV002104503	uncertain significance	Hereditary spastic paraplegia	2017-01-31	criteria provided, single submitter	clinical testing
OMIM	RCV000024154	SCV000045445	pathogenic	Neurodegeneration with brain iron accumulation 4	2011-10-07	flagged submission	literature only
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415210	SCV000492734	pathogenic	Dystonic disorder; Mental deterioration; Tremor; Adult-onset night blindness; Peripheral visual field loss	2015-07-01	flagged submission	clinical testing
GenomeConnect, ClinGen	RCV000509226	SCV000607239	not provided	Neurodegeneration with brain iron accumulation 4; Hereditary spastic paraplegia 43		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000553096	SCV001743246	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000553096	SCV001931725	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000553096	SCV001973835	likely benign	not provided		no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV000024154	SCV005091446	likely pathogenic	Neurodegeneration with brain iron accumulation 4	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team