Submissions for variant NM_014844.5(TECPR2):c.1981G>A (p.Glu661Lys)

gnomAD frequency: 0.00065  dbSNP: rs144915346

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000472228	SCV000548750	uncertain significance	Hereditary spastic paraplegia 49	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 661 of the TECPR2 protein (p.Glu661Lys). This variant is present in population databases (rs144915346, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of TECPR2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 408916). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000472228	SCV001528889	uncertain significance	Hereditary spastic paraplegia 49	2018-11-26	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV001507864	SCV001713684	uncertain significance	not provided	2020-12-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844164	SCV002103886	uncertain significance	not specified	2022-02-26	criteria provided, single submitter	clinical testing	Variant summary: TECPR2 c.1981G>A (p.Glu661Lys) 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 0.00063 in 249836 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TECPR2 causing Hereditary Spastic Paraplegia, Type 49 (0.00063 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1981G>A in individuals affected with Hereditary Spastic Paraplegia, Type 49 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848807	SCV002105923	uncertain significance	Hereditary spastic paraplegia	2020-11-25	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252133	SCV002523413	likely benign	See cases	2019-12-25	criteria provided, single submitter	clinical testing	ACMG classification criteria: BP1, BP4
GeneDx	RCV001507864	SCV002568562	uncertain significance	not provided	2022-08-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in association with a TECPR2-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 33206719)
Ambry Genetics	RCV002525577	SCV003684825	uncertain significance	Inborn genetic diseases	2023-04-17	criteria provided, single submitter	clinical testing	The c.1981G>A (p.E661K) alteration is located in exon 9 (coding exon 8) of the TECPR2 gene. This alteration results from a G to A substitution at nucleotide position 1981, causing the glutamic acid (E) at amino acid position 661 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000472228	SCV003827161	uncertain significance	Hereditary spastic paraplegia 49	2021-01-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001507864	SCV003917349	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	TECPR2: BP4
Natera, Inc.	RCV000472228	SCV001461378	uncertain significance	Hereditary spastic paraplegia 49	2020-04-16	no assertion criteria provided	clinical testing