chr2-39054763-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_005633.4(SOS1):c.571G>A(p.Glu191Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000567 in 1,586,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000558 AC: 8AN: 1434786Hom.: 0 Cov.: 28 AF XY: 0.00000279 AC XY: 2AN XY: 715574
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74272
ClinVar
Submissions by phenotype
not provided Uncertain:3
Reported in a patient with dilated cardiomyopathy; however, this patient also harbored potentially disease-causing variants in other genes associated with cardiomyopathy (PMID: 32603605); De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29493581, 29437595, 32603605) -
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Noonan syndrome 4 Pathogenic:1Uncertain:1
This variant was identified in a patient with visual deficits and sysmorphic stigmata in line with the diagnosis of Noonan syndrome. The variant was present at low-level mosaicism (VAF 2%) in the blood DNA of the mother. Applying PS2, PM2 and PP5 the variant meets our criteria to be classified as likely pathogenic. -
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not specified Uncertain:1
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Noonan syndrome Uncertain:1
The c.571G>A missense variant has a frequency of 0.000006984 (1 of 143,180 alleles) with a maximum allele frequency of 0.00002380 (1 of 42,014) in the African subpopulation. This does not been criteria for PM2 based on ClinGen's RASopathy Expert Panel consensus methods for variant interpretation (PMID: 29493581). The p.Glu191Lys variant has been identified somatically in a patient with JMML (PMID: 29437595). The variant has also been found to segregate in a pedigree with aggressive, early-onset dilated cardiomyopathy alongside an A-band TTN truncating variant, and individuals without the SOS1 variant demonstrated reduced disease severity, thus suggesting this variant's potential involvement as a genetic risk factor for dilated cardiomyopathy in this family (PMID: 32603605). Five of seven in silico tools predict a deleterious effect of this variant on protein function (PP3). In ERK activation studies, the p.Glu191Lys variant increased phosphorylated ERK expression relative to wild-type levels, paralleling known disease-relevant SOS1 signaling profiles (PS3; PMID: 32603605). In summary, the clinical significance of SOS1 c.571G>A (p.Glu191Lys) is uncertain based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): PS3, PP3. -
Primary dilated cardiomyopathy Uncertain:1
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Fibromatosis, gingival, 1 Uncertain:1
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RASopathy Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 191 of the SOS1 protein (p.Glu191Lys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32603605). ClinVar contains an entry for this variant (Variation ID: 40656). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at