Submissions for variant NM_006262.4(PRPH):c.421G>T (p.Asp141Tyr)

gnomAD frequency: 0.00373  dbSNP: rs58599399

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523206	SCV000617824	uncertain significance	not specified	2017-10-16	criteria provided, single submitter	clinical testing	The D141Y variant in the PRPH gene has been reported previously in the homozygous and heterozygous state in unrelated individuals with ALS (Leung et al., 2004; Corrado et al., 2011). The D141Y variant is observed in 373/64280 (0.58%) alleles in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The D141Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D141Y as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000057167	SCV001026516	likely benign	not provided	2019-12-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000057167	SCV001148731	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000523206	SCV004122463	uncertain significance	not specified	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: PRPH c.421G>T (p.Asp141Tyr) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 140550 control chromosomes. This frequency does not allow conclusions about variant significance due to lack of accurate figures supporting the prevalence of PRPH-associated Amyotrophic Lateral Sclerosis Type 1 and limited reported association of this gene with the phenotype (Clingen, 2022). Furthermore, low to variable penetrance, role as a susceptibility factor and possibility of pre-symptomatic individuals in the control populations have each been speculated (Gromicho_2020). c.421G>T has been reported in the literature in individuals affected with features of Familial Amyotrophic Lateral Sclerosis (FALS) and in unaffected controls (example, Gromicho_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Amyotrophic Lateral Sclerosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32638105). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=2; LB, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
OMIM	RCV000014706	SCV000034961	risk factor	Amyotrophic lateral sclerosis, susceptibility to	2004-07-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057167	SCV000088280	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV003964802	SCV004781482	likely benign	PRPH-related disorder	2020-01-21	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).