Submissions for variant NM_006767.4(LZTR1):c.1723G>A (p.Asp575Asn)

gnomAD frequency: 0.00061  dbSNP: rs139368531

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000876038	SCV001018545	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290562	SCV001478636	benign	not specified	2021-01-21	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1723G>A (p.Asp575Asn) results in a 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 0.00048 in 250384 control chromosomes. The observed variant frequency is approximately 96.6- fold the estimated maximal expected allele frequency for a pathogenic variant in LZTR1 causing Noonan Syndrome phenotype (5e-06), strongly suggesting that the variant is benign. To our knowledge, no reports of c.1723G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating an impact on protein function have been documented in the literature. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000876038	SCV001837951	likely benign	not provided	2019-09-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24362817)
Ambry Genetics	RCV002399962	SCV002714210	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-08-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV003948244	SCV004762862	likely benign	LZTR1-related condition	2022-03-02	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000876038	SCV001552405	uncertain significance	not provided		no assertion criteria provided	clinical testing	The LZTR1 p.Asp575Asn variant was not identified in the literature nor was it identified in ClinVar or Cosmic. The variant was identified in dbSNP (ID: rs139368531) and in LOVD 3.0. The variant was also identified in control databases in 139 of 281786 chromosomes at a frequency of 0.000493 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 74 of 24604 chromosomes (freq: 0.003008), Other in 7 of 7216 chromosomes (freq: 0.00097), European (non-Finnish) in 43 of 128774 chromosomes (freq: 0.000334), Latino in 11 of 35402 chromosomes (freq: 0.000311) and African in 4 of 24888 chromosomes (freq: 0.000161); it was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asp575 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.