Submissions for variant NM_001164508.2(NEB):c.24735_24736del (p.Arg8245fs)

dbSNP: rs776059611

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668220	SCV000792788	likely pathogenic	Nemaline myopathy 2	2017-07-14	criteria provided, single submitter	clinical testing
Invitae	RCV000668220	SCV001227086	pathogenic	Nemaline myopathy 2	2023-01-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552874). This variant is also known as c.24735_ 24736del. This premature translational stop signal has been observed in individual(s) with congenital nemaline myopathy (PMID: 24725366). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg8280Serfs*2) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138).
Illumina Laboratory Services, Illumina	RCV003126899	SCV003802798	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing	The NEB c.24735_24736del (p.Arg8245SerfsTer2) variant results in the deletion of two nucleotides at position c.24735, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant, also referred to as c.24840_24841del (p.Arg8280SerfsTer2), has been reported in a homozygous state in one individual with nemaline myopathy (PMID: 24725366). This variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000124 in the African/African American population (version 2.1.1). Based on the available evidence, the c.24735_24736del (p.Arg8245SerfsTer2) variant is classified as pathogenic for nemaline myopathy.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000668220	SCV003807419	pathogenic	Nemaline myopathy 2	2022-10-21	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 supporting
Baylor Genetics	RCV003465483	SCV004200172	pathogenic	Arthrogryposis multiplex congenita 6	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488790	SCV004241116	pathogenic	Nemaline myopathy	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: NEB c.24840_24841delAG (p.Arg8280SerfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 247816 control chromosomes. c.24840_24841delAG has been reported in the literature in individuals affected with Nemaline Myopathy 2 (eg. Malfatti_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV000668220	SCV002083953	pathogenic	Nemaline myopathy 2	2020-11-10	no assertion criteria provided	clinical testing