Submissions for variant NM_001330288.2(SMARCC2):c.3222del (p.Gly1075fs)

gnomAD frequency: 0.00002  dbSNP: rs752788954

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001280728	SCV001468043	uncertain significance	not provided	2020-09-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001280728	SCV001823353	uncertain significance	not provided	2025-02-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 37551667, 35982159, 36368308, 33004838, 35699097, 35982160)
New York Genome Center	RCV002227514	SCV002506975	uncertain significance	Coffin-Siris syndrome 8	2021-05-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002227514	SCV002806870	uncertain significance	Coffin-Siris syndrome 8	2022-01-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003405490	SCV004114962	uncertain significance	SMARCC2-related disorder	2022-12-20	criteria provided, single submitter	clinical testing	The SMARCC2 c.3129delT variant is predicted to result in a frameshift and premature protein termination (p.Gly1044Aspfs*17). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0077% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-56559111-CA-C). Although frameshift variants in SMARCC2 are expected to be pathogenic, this variant occurs in general population at higher frequency (7 heterozygotes) than expected for disease causing variant in autosomal dominant disorder. However, gnomaAD data in this region may not be accurate due to short homopolymer sequence in near proximity. This variant has been observed in at least three patients at PreventionGenetics with intellectual disability phenotypes. However, in one instance the variant was inherited from an apparently unaffected mother. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001280728	SCV005781854	uncertain significance	not provided	2024-03-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly1044Aspfs*17) in the SMARCC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMARCC2 are known to be pathogenic (PMID: 30580808). This variant is present in population databases (rs752788954, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with clinical features of SMARCC2-related conditions (PMID: 33004838, 35699097). ClinVar contains an entry for this variant (Variation ID: 992305). 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.