Submissions for variant NM_177924.5(ASAH1):c.629T>C (p.Met210Thr)

gnomAD frequency: 0.00098  dbSNP: rs141068211

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000275237	SCV000472715	uncertain significance	Farber lipogranulomatosis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Athena Diagnostics	RCV000710620	SCV000840866	likely benign	not provided	2019-06-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000710620	SCV001533230	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 210 of the ASAH1 protein (p.Met210Thr). This variant is present in population databases (rs141068211, 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 Rolandic epilepsy (PMID: 29358611). ClinVar contains an entry for this variant (Variation ID: 362376). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ASAH1 protein function. 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.
GeneDx	RCV000710620	SCV001802911	likely benign	not provided	2021-01-19	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29358611)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509374	SCV002819730	uncertain significance	not specified	2022-12-21	criteria provided, single submitter	clinical testing	Variant summary: ASAH1 c.629T>C (p.Met210Thr) results in a non-conservative amino acid change located in the Choloylglycine hydrolase/NAAA C-terminal domain (IPR029132) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 255942 control chromosomes (gnomAD and publication data). c.629T>C has been reported in the literature in individuals affected with lysosomal storage disorders, Parkinsons disease or Rolandic epilepsy, as well as in controls (Di Fruscio_2015, Robak_2017, Bobbili_2018). These reports do not provide unequivocal conclusions about association of the variant with Spinal Muscular Atrophy With Progressive Myoclonic Epilepsy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=2), likely benign (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002523650	SCV003650361	likely benign	Inborn genetic diseases	2021-03-30	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.
Revvity Omics, Revvity	RCV000710620	SCV003825059	uncertain significance	not provided	2022-06-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710620	SCV004042335	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000656011	SCV000588287	pathogenic	Childhood epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15
Clinical Genetics, Academic Medical Center	RCV000710620	SCV001925967	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000710620	SCV001971812	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549826	SCV004720343	likely benign	ASAH1-related disorders	2023-10-25	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).