Submissions for variant NM_018941.4(CLN8):c.806A>T (p.Glu269Val)

gnomAD frequency: 0.00016  dbSNP: rs139003032

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723601	SCV000229158	uncertain significance	not provided	2015-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000187131	SCV000240707	likely benign	not specified	2017-10-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084070	SCV000560190	benign	Neuronal ceroid lipofuscinosis	2024-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515342	SCV000611460	uncertain significance	Neuronal ceroid lipofuscinosis 8 northern epilepsy variant; Neuronal ceroid lipofuscinosis 8	2017-05-23	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000187131	SCV001984499	likely benign	not specified	2020-01-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000670572	SCV002060352	uncertain significance	Neuronal ceroid lipofuscinosis 8	2021-10-01	criteria provided, single submitter	clinical testing	NM_018941.3(CLN8):c.806A>T(E269V) is a missense variant classified as a variant of uncertain significance in the context of CLN8-related neuronal ceroid lipofuscinosis. E269V has been observed in cases with relevant disease (PMID: 28454995, 21990111). Functional assessments of this variant are not available in the literature. E269V has been observed in population frequency databases (gnomAD: SAS 0.06%). In summary, there is insufficient evidence to classify NM_018941.3(CLN8):c.806A>T(E269V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000187131	SCV002103938	uncertain significance	not specified	2024-08-01	criteria provided, single submitter	clinical testing	Variant summary: CLN8 c.806A>T (p.Glu269Val) results in a non-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 0.00033 in 251112 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CLN8 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (0.00033 vs 0.00087), allowing no conclusion about variant significance. c.806A>T has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease), including one patient in the homozygous state (Kousi_2011, Alfares_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28454995, 28468868, 21990111). ClinVar contains an entry for this variant (Variation ID: 196493). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252020	SCV002524038	uncertain significance	See cases	2019-06-17	criteria provided, single submitter	clinical testing	ACMG classification criteria: PP3, BS1
Mayo Clinic Laboratories, Mayo Clinic	RCV000723601	SCV002540918	uncertain significance	not provided	2021-05-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408767	SCV002675697	likely benign	Inborn genetic diseases	2019-07-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000723601	SCV004159391	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000670572	SCV001133075	likely pathogenic	Neuronal ceroid lipofuscinosis 8	2019-09-26	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000670572	SCV002083196	likely benign	Neuronal ceroid lipofuscinosis 8	2020-10-13	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537428	SCV004742667	likely benign	CLN8-related disorder	2022-10-19	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).