Submissions for variant NM_001271208.2(NEB):c.23881C>T (p.Pro7961Ser) (rs193224180)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000174649	SCV000225982	likely benign	not specified	2015-03-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000174649	SCV000272197	uncertain significance	not specified	2015-11-03	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Pro7961Ser va riant in NEB has not been previously reported in individuals with myopathy, but has been identified in 0.15% (97/66646) of European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193224180). C omputational prediction tools and conservation analysis do not provide strong su pport for or against an impact to the protein. In summary, while the clinical si gnificance of the p.Pro7961Ser variant is uncertain, these data suggest that it is more likely to be benign.
Invitae	RCV001080323	SCV000640729	likely benign	Nemaline myopathy 2	2020-12-05	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000556596	SCV001152432	uncertain significance	not provided	2016-05-01	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001080323	SCV001291480	uncertain significance	Nemaline myopathy 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Natera, Inc.	RCV001080323	SCV001454443	uncertain significance	Nemaline myopathy 2	2019-11-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000556596	SCV001554126	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NEB p.Pro7926Ser variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs193224180), ClinVar (classified as likely benign by EGL Genetics and as a VUS by Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine and Invitae for nemaline myopathy 2) and LOVD 3.0. The variant was identified in control databases in 316 of 280356 chromosomes at a frequency of 0.001127 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 (non-Finnish) in 260 of 128302 chromosomes (freq: 0.002026), Latino in 38 of 35298 chromosomes (freq: 0.001077), Other in 6 of 7122 chromosomes (freq: 0.000843), African in 8 of 24192 chromosomes (freq: 0.000331), European (Finnish) in 3 of 25010 chromosomes (freq: 0.00012) and Ashkenazi Jewish in 1 of 10348 chromosomes (freq: 0.000097); it was not observed in the East Asian and South Asian populations. The p.Pro7926 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.