ClinVar Genomic variation as it relates to human health

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported to be associated with [GeneName] related disorder (ClinVar ID: VCV000547999.8). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

PVS2, PS2, PM2

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33144682, 30345613, 26785492, 32368696, 33084842)

The de novo c.1676_1679del variant identified in the NSD2 gene has previously been reported as de novo variant in individuals with NSD2-related disorder with features of developmental delay, cardiac defects, and multiple congenital malformations [PMID: 30345613, 26785492, 33144682] and it has been deposited in ClinVar [ClinVar ID: 547999] as Pathogenic. The c.1676_1679del variant is observed in 1 allele (~0.00062% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.1676_1679del variant in NSD2 is located in exon 8 of this 22-exon gene, predicted to incorporate a premature termination codon approximately 38 amino acids downstream (p.(Arg559ThrfsTer38)), and is expected to result in loss-of-function via nonsense mediated decay. Multiple loss-of-function variants that are downstream to the c.1676_1679del variant have been reported in the literature [PMID: 31382906, 33941880] and ClinVar [ClinVar ID: 1333177] in individuals with Rauch-Steindl syndrome. Based on available evidence this de novo c.1676_1679del (p.(Arg559ThrfsTer38)), variant identified in NSD2 is classified here as Pathogenic.

The NSD2 c.1676_1679delGAGA variant is predicted to result in a frameshift and premature protein termination (p.Arg559Thrfs*38). This variant was reported de novo in at least one individual with congenital heart disease (as 4:1940175 TAGAG>T in WHSC1; Dataset S2, Homsy et al. 2015. PubMed ID: 26785492; Dataset S2, Sevim Bayrak et al. 2020. PubMed ID: 31941532; Edwards et al. 2020. PubMed ID: 32368696; eTable 4, Morton et al. 2021. PubMed ID: 33084842) and also was reported de novo in at least one individual with developmental delays, mild facial dysmorphisms, short stature, failure to thrive, and microcephaly (as: c.1676_1679del (p.Arg559Tfs*38) in WHSC1; Boczek et al. 2018. PubMed ID: 30345613; Klee et al. 2020. PubMed ID: 33144682). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in NSD2 are expected to be pathogenic. This variant is interpreted as likely pathogenic.