Submissions for variant NM_006767.4(LZTR1):c.1943-256C>T

gnomAD frequency: 0.00009  dbSNP: rs761685529

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000735432	SCV000746562	uncertain significance	Noonan syndrome 2	2017-05-01	criteria provided, single submitter	clinical testing	This family has been reported in PMID:29469822.
GeneDx	RCV000681140	SCV000808598	pathogenic	not provided	2022-02-11	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in loss-of-function; inclusion of 117bp from an alternate exon lead to a truncated protein, p.(T648fs*36), that was subject to nonsense mediated decay (Johnston et al., 2018; Hanses et al. 2020); This variant is associated with the following publications: (PMID: 29469822, 32623905, 34747535)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000735432	SCV001445972	pathogenic	Noonan syndrome 2	2023-05-02	criteria provided, single submitter	curation	The heterozygous c.1943-256C>T variant in LZTR1 was identified by our study in the compound heterozygous state, along with another likely pathogenic variant, in 2 siblings with Noonan syndrome 2. The variant has been reported in 8 individuals of unknown ethnicity with Noonan syndrome 2 (PMID: 29469822, 32623905) and segregated with disease in 4 affected relatives from 3 families (PMID: 29469822, 32623905). This variant has been identified in 0.019% (3/15796) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs761685529). Although the c.1943-256C>T variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 522800) as pathogenic by OMIM and GeneDx, and as having unknown significance by the Undiagnosed Diseases Network, NIH. Of the 10 affected individuals, 2 of those were homozygotes, 5 were compound heterozygotes that carried a reported pathogenic/likely pathogenic variants in trans, and 3 were compound heterozygotes that carried a variants of uncertain significance in trans, which increases the likelihood that the c.1943-256C>T variant is pathogenic (VariationID: 522799, 372684; PMID: 29469822, 32623905). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 29469822, 32623905). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Noonan syndrome 2. ACMG/AMP Criteria applied: PM3_strong, PP1_strong, PS3_moderate (Richards 2015).
Ambry Genetics	RCV002413779	SCV002719307	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-10-20	criteria provided, single submitter	clinical testing	The c.1943-256C>T intronic pathogenic mutation results from a C to T substitution 256 nucleotides upstream from coding exon 17 in the LZTR1 gene. This alteration has been reported in multiple individuals with autosomal recessive Noonan syndrome in trans with other mutations or in the homozygous state and was shown to segregate with disease in several families (Johnston JJ et al. Genet Med. 2018 Oct;20(10):1175-1185). RNA studies demonstrated that this alteration results in the retention of a 117-base pair alternate exon that lies within intron 16 (Johnston JJ et al. Genet Med. 2018 Oct;20(10):1175-1185; Hanses U et al. Circulation, 2020 Sep;142:1059-1076; Ambry internal data). Based on the supporting evidence, this variant is pathogenic for an increased risk of LZTR1-related schwannomatosis (SWN) and would be expected to cause autosomal recessive Noonan syndrome when present along with a second pathogenic or likely pathogenic variant on the other allele.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000735432	SCV002766330	pathogenic	Noonan syndrome 2	2022-11-11	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1943-256C>T is located within intron 16 at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic 5' donor site. At least two publications report experimental evidence that this variant indeed affects mRNA splicing, resulting in the inclusion of the additional 117 bp cryptic exon between exons 16 and 17 (e.g. Johnston_2018, Hanses_2020). The variant allele was found at a frequency of 4.1e-05 in 147296 control chromosomes (gnomAD). c.1943-256C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Noonan Syndrome 2 from at least five different families in which the variant was found to segregate with the disease in an autosomal recessive pattern of inheritance (e.g. Johnston_2018, Hanses_2020). These data indicate that the variant is very likely to be associated with disease. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as pathogenic (n=3) and one classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000681140	SCV003021760	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 16 of the LZTR1 gene. It does not directly change the encoded amino acid sequence of the LZTR1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs761685529, gnomAD 0.02%). This variant has been observed in individuals with Noonan syndrome (PMID: 29469822, 32623905). ClinVar contains an entry for this variant (Variation ID: 522800). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 29469822, 32623905). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003336096	SCV004046353	pathogenic	Noonan syndrome		criteria provided, single submitter	clinical testing	This variant has been previously reported as a homozygous and compound heterozygous change in individuals with Noonan syndrome and shown to moderately segregate with disease in two families (PMID: 29469822). Heterozygous carrier parents demonstrated mild or no clinical manifestations (PMID: 29469822). Splicing studies using the RNA from a patient's lymphoblasts showed an abnormal product retaining a 117bp sequence from intron 16 (PMID: 29469822). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (11/178598) and is absent in the homozygous state, and thus is presumed to be rare. Based on the available evidence, the c.1943-256C>T variant is classified as Pathogenic.
Baylor Genetics	RCV003465362	SCV004191286	pathogenic	Schwannomatosis 2	2023-12-21	criteria provided, single submitter	clinical testing
OMIM	RCV000735432	SCV000863567	pathogenic	Noonan syndrome 2	2018-12-17	no assertion criteria provided	literature only