Submissions for variant NM_022455.5(NSD1):c.1477C>G (p.Pro493Ala)

gnomAD frequency: 0.00009  dbSNP: rs375051877

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001692166	SCV001492147	benign	not provided	2022-09-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001692166	SCV001910954	likely benign	not provided	2019-11-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003231633	SCV002054986	likely benign	Sotos syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330747	SCV004037620	likely benign	not specified	2023-08-03	criteria provided, single submitter	clinical testing	Variant summary: NSD1 c.1477C>G (p.Pro493Ala) 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 5e-05 in 282496 control chromosomes (i.e. 14 heterozygotes) in gnomAD v2.1. The relatively high number of carriers suggests a benign role for this variant for an early onset, high penetrance dominant disease phenotype. To our knowledge, no occurrence of c.1477C>G in individuals affected with Sotos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV005372344	SCV006036574	likely benign	Inborn genetic diseases	2025-01-22	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.
PreventionGenetics, part of Exact Sciences	RCV003962458	SCV004781198	likely benign	NSD1-related disorder	2023-11-14	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).