Submissions for variant NM_138361.5(LRSAM1):c.2003_2015del (p.Leu668fs) (rs876661208)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214054	SCV000279792	likely pathogenic	not provided	2016-01-22	criteria provided, single submitter	clinical testing	The c.2003_2015del13 variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.2003_2015del13 variant causes a frameshift starting with codon Leucine 668, changes this amino acid to a Proline residue and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Leu668ProfsX14. This variant is predicted to cause loss of normal protein function through protein truncation as the last 56 amino acids of the LRSAM1 protein are lost and replaced with 13 incorrect amino acids. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000696532	SCV000825096	likely pathogenic	Charcot-Marie-Tooth disease type 2P	2018-05-17	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the LRSAM1 gene (p.Leu668Profs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acids of the LRSAM1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LRSAM1-related disease. ClinVar contains an entry for this variant (Variation ID: 234769). Other truncations (c.2021_2024del, c.2043_2044dupGG and c.2047-1G>A) that lie downstream of this variant have been reported in individuals affected with autosomal dominant Charcot-Marie-Tooth disease (PMID:29341362, 22781092, 28286897, Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.